Nordberg A

General

Full name : Nordberg Agneta

First name : Agneta

Mail : Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, NOVUM, 4th Floor, 141 86 Stockholm

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Country : Sweden

Email : Agneta.K.Nordberg@ki.se

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Website : \/\/ki.se\/en\/nvs\/portrait-of-professor-agneta-nordberg

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References (154)

Title : The role of astrocytic alpha7 nicotinic acetylcholine receptors in Alzheimer disease - Fontana_2023_Nat.Rev.Neurol__
Author(s) : Fontana IC , Kumar A , Nordberg A
Ref : Nat Rev Neurol , : , 2023
Abstract : The ongoing search for therapeutic interventions in Alzheimer disease (AD) has highlighted the complexity of this condition and the need for additional biomarkers, beyond amyloid-beta (Abeta) and tau, to improve clinical assessment. Astrocytes are brain cells that control metabolic and redox homeostasis, among other functions, and are emerging as an important focus of AD research owing to their swift response to brain pathology in the initial stages of the disease. Reactive astrogliosis - the morphological, molecular and functional transformation of astrocytes during disease - has been implicated in AD progression, and the definition of new astrocytic biomarkers could help to deepen our understanding of reactive astrogliosis along the AD continuum. As we highlight in this Review, one promising biomarker candidate is the astrocytic alpha7 nicotinic acetylcholine receptor (alpha7nAChR), upregulation of which correlates with Abeta pathology in the brain of individuals with AD. We revisit the past two decades of research into astrocytic alpha7nAChRs to shed light on their roles in the context of AD pathology and biomarkers. We discuss the involvement of astrocytic alpha7nAChRs in the instigation and potentiation of early Abeta pathology and explore their potential as a target for future reactive astrocyte-based therapeutics and imaging biomarkers in AD.
ESTHER : Fontana_2023_Nat.Rev.Neurol__
PubMedSearch : Fontana_2023_Nat.Rev.Neurol__
PubMedID: 36977843

Title : Clinical impact of [(18)F]flutemetamol PET among memory clinic patients with an unclear diagnosis - Leuzy_2019_Eur.J.Nucl.Med.Mol.Imaging_46_1276
Author(s) : Leuzy A , Savitcheva I , Chiotis K , Lilja J , Andersen P , Bogdanovic N , Jelic V , Nordberg A
Ref : Eur J Nucl Med Mol Imaging , 46 :1276 , 2019
Abstract : PURPOSE: To investigate the impact of amyloid PET with [(18)F]flutemetamol on diagnosis and treatment management in a cohort of patients attending a tertiary memory clinic in whom, despite extensive cognitive assessment including neuropsychological testing, structural imaging, CSF biomarker analysis and in some cases [(18)F]FDG PET, the diagnosis remained unclear. METHODS: The study population consisted of 207 patients with a clinical diagnosis prior to [(18)F]flutemetamol PET including mild cognitive impairment (MCI; n = 131), Alzheimer's disease (AD; n = 41), non-AD (n = 10), dementia not otherwise specified (dementia NOS; n = 20) and subjective cognitive decline (SCD; n = 5). RESULTS: Amyloid positivity was found in 53% of MCI, 68% of AD, 20% of non-AD, 20% of dementia NOS, and 60% of SCD patients. [(18)F]Flutemetamol PET led, overall, to a change in diagnosis in 92 of the 207 patients (44%). A high percentage of patients with a change in diagnosis was observed in the MCI group (n = 67, 51%) and in the dementia NOS group (n = 11; 55%), followed by the non-AD and AD (30% and 20%, respectively). A significant increase in cholinesterase inhibitor treatment was observed after [(18)F]flutemetamol PET (+218%, 34 patients before and 108 patients after). CONCLUSION: The present study lends support to the clinical value of amyloid PET in patients with an uncertain diagnosis in the tertiary memory clinic setting.
ESTHER : Leuzy_2019_Eur.J.Nucl.Med.Mol.Imaging_46_1276
PubMedSearch : Leuzy_2019_Eur.J.Nucl.Med.Mol.Imaging_46_1276
PubMedID: 30915522

Title : CSF Cholinergic Index, a New Biomeasure of Treatment Effect in Patients With Alzheimer's Disease - Karami_2019_Front.Mol.Neurosci_12_239
Author(s) : Karami A , Eriksdotter M , Kadir A , Almkvist O , Nordberg A , Darreh-Shori T
Ref : Front Mol Neurosci , 12 :239 , 2019
Abstract : Alzheimer's disease (AD) is a progressive disease with early degeneration of the central cholinergic neurons. Currently, three of four AD drugs act by inhibiting the acetylcholine (ACh) degrading enzyme, acetylcholinesterase (AChE). Efficacy of these drugs depends on available amount of ACh, which is biosynthesized by choline acetyltransferase (ChAT). We investigated whether treatment with a cholinesterase-inhibitor, galantamine, alters the relative levels of AChE to ChAT in cerebrospinal fluid (CSF) and whether levels of these CSF biomarkers correlate with in vivo AChE activity and nicotinic binding sites in the brain assessed by positron emission tomography (PET). Protein concentrations and activities of ChAT and AChE were measured in CSF of 18 patients with mild AD prior to and after 3 months of treatment with galantamine (n = 12) or placebo (n = 6), followed by nine additional months of galantamine treatment in all patients. A Cholinergic index was defined as the ratio of ChAT to AChE in CSF and was evaluated in relation to the in vivo AChE activity, the nicotinic binding sites and different measures of cognition. Besides an expected inhibition of AChE activity, galantamine treatment was accompanied by a mild increase in CSF ChAT activity. Thereby, the Cholinergic index was significantly increased in the Galantamine group (60% +/- 14) after 3 months compared to baseline (p < 0.0023) or (p < 0.0004). This index remained high in the Galantamine group compared to baseline (54% +/- 11) at 12 months follow-up, while it showed an increase in the Placebo group when they switched to active galantamine treatment (44% +/- 14 vs. baseline, 61% +/- 14 vs. 3 months, all p-values < 0.05). Furthermore, the in vivo brain AChE activity (assessed by PET) correlated with the CSF Cholinergic index at 12 months (r = 0.98, p < 0.001). The CSF Cholinergic index also correlated with ADAS-Cog and some other neuropsychological tests at 12 months. This is the first study assessing a CSF Cholinergic index in relation to treatment with a cholinesterase inhibitor. The treatment-specific increase in CSF ChAT activity suggests that cholinesterase-inhibitors may also increase the ACh-biosynthesis capacity in the patients. Additional studies are warranted to evaluate the utility of the CSF Cholinergic index as a biomeasure of therapeutic effect in AD.
ESTHER : Karami_2019_Front.Mol.Neurosci_12_239
PubMedSearch : Karami_2019_Front.Mol.Neurosci_12_239
PubMedID: 31680850

Title : Homomeric and Heteromeric Abeta Species Exist in Human Brain and CSF Regardless of Alzheimer's Disease Status and Risk Genotype - Lana_2019_Front.Mol.Neurosci_12_176
Author(s) : Lana E , Gellerbring A , Jung S , Nordberg A , Unger Lithner C , Darreh-Shori T
Ref : Front Mol Neurosci , 12 :176 , 2019
Abstract : Background: A fundamental question in Alzheimer's disease (AD) is whether amyloid-beta (Abeta) peptides and their deposition in the brain signify a direct pathological role or they are mere outcome of the disease pathophysiological events affecting neuronal function. It is therefore important to decipher their physiological role in the brain. So far, the overwhelming focus has been on the potential toxicity of Abeta, often studied outside the crucial AD characteristics, i.e.: (i) the slow, decades-long disease progression that precedes clinical symptoms; (ii) the link to apolipoprotein-E epsilon4 allele as major risk factor; (iii) the selective early degeneration of cholinergic neurons. Previous studies, in vitro and cerebrospinal fluid (CSF) only, indicated one possible native function of Abeta peptides is the allosteric modulation of acetylcholine homeostasis, via molecular interactions between Abeta, apolipoprotein-E, and the acetylcholine-degrading enzymes, cholinesterases, resulting in the formation of acetylcholine-hydrolyzing complexes (BAbetaACs). Methods: Here, by combining sucrose-density gradient fractionation of post-mortem brains and in-house developed sensitive ELISA assays on the obtained fractions, we investigated the presence, levels and molecular interactions between Abeta, apolipoprotein-E and cholinesterases for the first time in brain tissues. We examined three distinct brain regions of Alzheimer and non-demented subjects, plus a large number of Alzheimer CSF samples. Results: We report that both monomeric and oligomeric (homomeric and heteromeric) forms of Abeta peptides are present in the brain of Alzheimer and non-demented individuals. Heteromeric Abeta was found in stable complexes with apolipoprotein-E and/or cholinesterases, irrespective of APOE genotype or disease status, arguing in favor of a physiological dynamic formation and function for these complexes in the brain. The patterns and molecular sizes of the detected soluble Abeta forms were closely matched between CSF and brain samples. This evinces that the detected Abeta-apolipoprotein-E complexes and BAbetaACs in CSF most likely originate from the interstitial fluids of the brain. Conclusions: In conclusion, both light homomeric Abeta oligomers and heteromeric Abeta-ApoE and BAbetaACs are present and readily detectable in the brain, regardless of disease status and APOE4 genotype. Deeper knowledge of the physiological function of Abeta is crucial for better understanding the early pathological events that decades later lead to manifestation of AD.
ESTHER : Lana_2019_Front.Mol.Neurosci_12_176
PubMedSearch : Lana_2019_Front.Mol.Neurosci_12_176
PubMedID: 31417354

Title : Amyloid-beta peptides act as allosteric modulators of cholinergic signalling through formation of soluble BAbetaACs - Kumar_2016_Brain_139_174
Author(s) : Kumar R , Nordberg A , Darreh-Shori T
Ref : Brain , 139 :174 , 2016
Abstract : Amyloid-beta peptides, through highly sophisticated enzymatic machinery, are universally produced and released in an action potential synchronized manner into the interstitial fluids in the brain. Yet no native functions are attributed to amyloid-beta. The amyloid-beta hypothesis ascribes just neurotoxicity properties through build-up of soluble homomeric amyloid-beta oligomers or fibrillar deposits. Apolipoprotein-epsilon4 (APOE4) allele is the only confirmed genetic risk factor of sporadic Alzheimer's disease; once more it is unclear how it increases the risk of Alzheimer's disease. Similarly, central cholinergic signalling is affected selectively and early in the Alzheimer's disease brain, again why cholinergic neurons show this sensitivity is still unclear. However, the three main known Alzheimer's disease risk factors, advancing age, female gender and APOE4, have been linked to a high apolipoprotein-E and accumulation of the acetylcholine degrading enzyme, butyrylcholinesterase in cerebrospinal fluids of patients. Furthermore, numerous reports indicate that amyloid-beta interacts with butyrylcholinesterase and apolipoprotein-E. We have proposed that this interaction leads to formation of soluble ultrareactive acetylcholine-hydrolyzing complexes termed BAbetaACs, to adjust at demand both synaptic and extracellular acetylcholine signalling. This hypothesis predicted presence of acetylcholine-synthesizing enzyme, choline acetyltransferase in extracellular fluids to allow maintenance of equilibrium between breakdown and synthesis of acetylcholine through continuous in situ syntheses. A recent proof-of-concept study led to the discovery of this enzyme in the human extracellular fluids. We report here that apolipoprotein-E, in particular epsilon4 isoprotein acts as one of the strongest endogenous anti-amyloid-beta fibrillization agents reported in the literature. At biological concentrations, apolipoprotein-E prevented amyloid-beta fibrillization for at least 65 h. We show that amyloid-beta interacts readily in an apolipoprotein-facilitated manner with butyrylcholinesterase, forming highly stable and soluble complexes, BAbetaACs, which can be separated in their native states by sucrose density gradient technique. Enzymological analyses further evinced that amyloid-beta concentration dependently increased the acetylcholine-hydrolyzing capacity of cholinesterases. In silico biomolecular analysis further deciphered the allosteric amino acid fingerprint of the amyloid-beta-cholinesterase molecular interaction in formation of BAbetaACs. In the case of butyrylcholinesterase, the results indicated that amyloid-beta interacts with a putative activation site at the mouth of its catalytic tunnel, most likely leading to increased acetylcholine influx into the catalytic site, and thereby increasing the intrinsic catalytic rate of butyrylcholinesterase. In conclusion, at least one of the native physiological functions of amyloid-beta is allosteric modulation of the intrinsic catalytic efficiency of cholinesterases, and thereby regulation of synaptic and extrasynaptic cholinergic signalling. High apolipoprotein-E may pathologically alter the biodynamics of this amyloid-beta function.
ESTHER : Kumar_2016_Brain_139_174
PubMedSearch : Kumar_2016_Brain_139_174
PubMedID: 26525916

Title : Targeted delivery of nerve growth factor to the cholinergic basal forebrain of Alzheimer's disease patients: application of a second-generation encapsulated cell biodelivery device - Eyjolfsdottir_2016_Alzheimers.Res.Ther_8_30
Author(s) : Eyjolfsdottir H , Eriksdotter M , Linderoth B , Lind G , Juliusson B , Kusk P , Almkvist O , Andreasen N , Blennow K , Ferreira D , Westman E , Nennesmo I , Karami A , Darreh-Shori T , Kadir A , Nordberg A , Sundstrom E , Wahlund LO , Wall A , Wiberg M , Winblad B , Seiger A , Wahlberg L , Almqvist P
Ref : Alzheimers Res Ther , 8 :30 , 2016
Abstract : BACKGROUND: Targeted delivery of nerve growth factor (NGF) has emerged as a potential therapy for Alzheimer's disease (AD) due to its regenerative effects on basal forebrain cholinergic neurons. This hypothesis has been tested in patients with AD using encapsulated cell biodelivery of NGF (NGF-ECB) in a first-in-human study. We report our results from a third-dose cohort of patients receiving second-generation NGF-ECB implants with improved NGF secretion.
METHODS: Four patients with mild to moderate AD were recruited to participate in an open-label, phase Ib dose escalation study with a 6-month duration. Each patient underwent stereotactic implant surgery with four NGF-ECB implants targeted at the cholinergic basal forebrain. The NGF secretion of the second-generation implants was improved by using the Sleeping Beauty transposon gene expression technology and an improved three-dimensional internal scaffolding, resulting in production of about 10 ng NGF/device/day.
RESULTS: All patients underwent successful implant procedures without complications, and all patients completed the study, including implant removal after 6 months. Upon removal, 13 of 16 implants released NGF, 8 implants released NGF at the same rate or higher than before the implant procedure, and 3 implants failed to release detectable amounts of NGF. Of 16 adverse events, none was NGF-, or implant-related. Changes from baseline values of cholinergic markers in cerebrospinal fluid (CSF) correlated with cortical nicotinic receptor expression and Mini Mental State Examination score. Levels of neurofilament light chain (NFL) protein increased in CSF after NGF-ECB implant, while glial fibrillary acidic protein (GFAP) remained stable.
CONCLUSIONS: The data derived from this patient cohort demonstrate the safety and tolerability of sustained NGF release by a second-generation NGF-ECB implant to the basal forebrain, with uneventful surgical implant and removal of NGF-ECB implants in a new dosing cohort of four patients with AD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01163825 . Registered on 14 Jul 2010.
ESTHER : Eyjolfsdottir_2016_Alzheimers.Res.Ther_8_30
PubMedSearch : Eyjolfsdottir_2016_Alzheimers.Res.Ther_8_30
PubMedID: 27389402

Title : Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer's disease - Karami_2015_Alzheimers.Dement_11_1316
Author(s) : Karami A , Eyjolfsdottir H , Vijayaraghavan S , Lind G , Almqvist P , Kadir A , Linderoth B , Andreasen N , Blennow K , Wall A , Westman E , Ferreira D , Kristoffersen Wiberg M , Wahlund LO , Seiger A , Nordberg A , Wahlberg L , Darreh-Shori T , Eriksdotter M
Ref : Alzheimers Dement , 11 :1316 , 2015
Abstract : INTRODUCTION: The extensive loss of central cholinergic functions in Alzheimer's disease (AD) brain is linked to impaired nerve growth factor (NGF) signaling. The cardinal cholinergic biomarker is the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT), which has recently been found in cerebrospinal fluid (CSF). The purpose of this study was to see if EC-NGF therapy will alter CSF levels of cholinergic biomarkers, ChAT, and acetylcholinesterase. METHOD: Encapsulated cell implants releasing NGF (EC-NGF) were surgically implanted bilaterally in the basal forebrain of six AD patients for 12 months and cholinergic markers in CSF were analyzed.
RESULTS: Activities of both enzymes were altered after 12 months. In particular, the activity of soluble ChAT showed high correlation with cognition, CSF tau and amyloid-beta, in vivo cerebral glucose utilization and nicotinic binding sites, and morphometric and volumetric magnetic resonance imaging measures. DISCUSSION: A clear pattern of association is demonstrated showing a proof-of-principle effect on CSF cholinergic markers, suggestive of a beneficial EC-NGF implant therapy.
ESTHER : Karami_2015_Alzheimers.Dement_11_1316
PubMedSearch : Karami_2015_Alzheimers.Dement_11_1316
PubMedID: 25676388

Title : Pharmacodynamics of Cholinesterase Inhibitors Suggests Add-on Therapy with a Low-Dose Carbamylating Inhibitor in Patients on Long-Term Treatment with Rapidly Reversible Inhibitors - Darreh-Shori_2014_J.Alzheimers.Dis_39_423
Author(s) : Darreh-Shori T , Hosseini SM , Nordberg A
Ref : J Alzheimers Dis , 39 :423 , 2014
Abstract : Despite three decades of intensive research in the field of Alzheimer's disease (AD) and numerous clinical trials of new therapeutic agents, cholinesterase inhibitors (ChEIs) are still the mainstay of therapeutics for AD and dementia with Lewy bodies. Pharmacodynamic analyses of ChEIs provide paradoxical observations. Treatment with the rapidly reversible, noncarbamylating ChEIs (donepezil, galantamine, and tacrine) increases acetylcholinesterase (AChE) protein expression, whereas the carbamylating agent, rivastigmine, produces sustained inhibition with no significant change in AChE protein expression. Still, the symptomatic clinical efficacies of all these agents are similar. We report here for the first time that treatment with phenserine, another carbamylating ChEI, produces a sustained but mild inhibition of AChE in cerebrospinal fluid (CSF) of AD patients. We also show that phenserine treatment reverses donepezil-induced elevation of AChE expression. Further analyses on CSF of another larger patient cohort treated with donepezil revealed that, in addition to its main mode of action, donepezil produced two other pharmacodynamics with potentially contradictory outcomes. Donepezil-induced AChE expression favored an AChE-driven amyloid-beta peptide (Abeta) aggregation, whereas donepezil itself concentration-dependently counteracted the AChE-induced Abeta aggregation, most likely by competing with the Abeta peptides for peripheral anionic site on the AChE protein. The reduction of AChE protein expression in the donepezil-treated patients by concomitant administration of the carbamylating agent, phenserine, could allow the donepezil molecule to only prevent interaction between Abeta and AChE. The current study suggests that an add-on therapy with a low-dose formulation of a carbamylating agent in patients on long-term donepezil treatment should be explored as a strategy for enhancing the clinical efficacy of these agents in dementia disorders.
ESTHER : Darreh-Shori_2014_J.Alzheimers.Dis_39_423
PubMedSearch : Darreh-Shori_2014_J.Alzheimers.Dis_39_423
PubMedID: 24217282

Title : Modulation of alpha7 Nicotinic Acetylcholine Receptor and Fibrillar Amyloid-beta Interactions in Alzheimer's Disease Brain - Ni_2013_J.Alzheimers.Dis_33_841
Author(s) : Ni R , Marutle A , Nordberg A
Ref : J Alzheimers Dis , 33 :841 , 2013
Abstract : The nicotinic receptors (nAChRs), which play a critical role in cognitive function, are impaired early in the course of Alzheimer's disease (AD). We have previously demonstrated that amyloid-beta (Abeta) assemblies bind to alpha7 nAChRs and form complexes in AD brain, suggesting that this cooperative process may contribute to disruption of synaptic function in AD. In the current study, we further characterized the interaction between different nAChR subtypes and fibrillar Abeta by binding assays in postmortem brain from AD and control cases using a wide range of drugs with different molecular targets, including selective nAChR subtype agonists, and the amyloid ligand Pittsburgh compound B (PIB) that binds with high (nanomolar) affinity to fibrillar Abeta. The alpha7 nAChR agonists varenicline and JN403, but not the alpha4beta2 nAChR agonist cytisine, increased the 3H-PIB binding in autopsy tissue homogenates from AD and control frontal cortex. This effect was blocked in the presence of the alpha7 nAChR antagonists methyllycaconitine, alpha-bungarotoxin, and mecamylamine, but not by the alpha4beta2 nAChR antagonist dihydro-beta-erythroidine. Increases in 3H-PIB binding evoked by varenicline and JN403 were also prevented by pre-incubation with another amyloid ligand, BF-227. The acetylcholinesterase inhibitor and allosteric nAChR modulator galantamine as well as the N-methyl-d-aspartate receptor blocker memantine did not significantly alter 3H-PIB binding levels in AD brain. The present findings further support a specific interaction between fibrillar Abeta and alpha7 nAChRs in the brain, suggesting that treatment with alpha7 nAChR stimulatory drugs can modulate Abeta/alpha7 nAChR pathogenic signaling mechanisms in AD brain.
ESTHER : Ni_2013_J.Alzheimers.Dis_33_841
PubMedSearch : Ni_2013_J.Alzheimers.Dis_33_841
PubMedID: 23042213

Title : Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer's disease - Darreh-Shori_2013_Neurobiol.Aging_34_2465
Author(s) : Darreh-Shori T , Vijayaraghavan S , Aeinehband S , Piehl F , Lindblom RP , Nilsson B , Ekdahl KN , Langstrom B , Almkvist O , Nordberg A
Ref : Neurobiology of Aging , 34 :2465 , 2013
Abstract : Butyrylcholinesterase (BCHE) activity is associated with activated astrocytes in Alzheimer's disease brain. The BCHE-K variant exhibits 30%-60% reduced acetylcholine (ACh) hydrolyzing capacity. Considering the increasing evidence of an immune-regulatory role of ACh, we investigated if genetic heterogeneity in BCHE affects cerebrospinal fluid (CSF) biomarkers of inflammation and cholinoceptive glial function. Alzheimer's disease patients (n = 179) were BCHE-K-genotyped. Proteomic and enzymatic analyses were performed on CSF and/or plasma. BCHE genotype was linked with differential CSF levels of glial fibrillary acidic protein, S100B, interleukin-1beta, and tumor necrosis factor (TNF)-alpha. BCHE-K noncarriers displayed 100%-150% higher glial fibrillary acidic protein and 64%-110% higher S100B than BCHE-K carriers, who, in contrast, had 40%-80% higher interleukin-1beta and 21%-27% higher TNF-alpha compared with noncarriers. A high level of CSF BCHE enzymatic phenotype also significantly correlated with higher CSF levels of astroglial markers and several factors of the innate complement system, but lower levels of proinflammatory cytokines. These individuals also displayed beneficial paraclinical and clinical findings, such as high cerebral glucose utilization, low beta-amyloid load, and less severe progression of clinical symptoms. In vitro analysis on human astrocytes confirmed the involvement of a regulated BCHE status in the astroglial responses to TNF-alpha and ACh. Histochemical analysis in a rat model of nerve injury-induced neuroinflammation, showed focal assembly of astroglial cells in proximity of BCHE-immunolabeled sites. In conclusion, these results suggest that BCHE enzymatic activity plays an important role in regulating intrinsic inflammation and activity of cholinoceptive glial cells and that this might be of clinical relevance. The dissociation between astroglial markers and inflammatory cytokines indicates that a proper activation and maintenance of astroglial function is a beneficial response, rather than a disease-driving mechanism. Further studies are needed to explore the therapeutic potential of manipulating BCHE activity or astroglial functional status.
ESTHER : Darreh-Shori_2013_Neurobiol.Aging_34_2465
PubMedSearch : Darreh-Shori_2013_Neurobiol.Aging_34_2465
PubMedID: 23759148

Title : Amyloid tracers detect multiple binding sites in Alzheimer's disease brain tissue - Ni_2013_Brain_136_2217
Author(s) : Ni R , Gillberg PG , Bergfors A , Marutle A , Nordberg A
Ref : Brain , 136 :2217 , 2013
Abstract : Imaging fibrillar amyloid-beta deposition in the human brain in vivo by positron emission tomography has improved our understanding of the time course of amyloid-beta pathology in Alzheimer's disease. The most widely used amyloid-beta imaging tracer so far is (11)C-Pittsburgh compound B, a thioflavin derivative but other (11)C- and (18)F-labelled amyloid-beta tracers have been studied in patients with Alzheimer's disease and cognitively normal control subjects. However, it has not yet been established whether different amyloid tracers bind to identical sites on amyloid-beta fibrils, offering the same ability to detect the regional amyloid-beta burden in the brains. In this study, we characterized (3)H-Pittsburgh compound B binding in autopsied brain regions from 23 patients with Alzheimer's disease and 20 control subjects (aged 50 to 88 years). The binding properties of the amyloid tracers FDDNP, AV-45, AV-1 and BF-227 were also compared with those of (3)H-Pittsburgh compound B in the frontal cortices of patients with Alzheimer's disease. Saturation binding studies revealed the presence of high- and low-affinity (3)H-Pittsburgh compound B binding sites in the frontal cortex (Kd1: 3.5 +/- 1.6 nM; Kd2: 133 +/- 30 nM) and hippocampus (Kd1:5.6 +/- 2.2 nM; Kd2: 181 +/- 132 nM) of Alzheimer's disease brains. The relative proportion of high-affinity to low-affinity sites was 6:1 in the frontal cortex and 3:1 in the hippocampus. One control showed both high- and low-affinity (3)H-Pittsburgh compound B binding sites (Kd1: 1.6 nM; Kd2: 330 nM) in the cortex while the others only had a low-affinity site (Kd2: 191 +/- 70 nM). (3)H-Pittsburgh compound B binding in Alzheimer's disease brains was higher in the frontal and parietal cortices than in the caudate nucleus and hippocampus, and negligible in the cerebellum. Competitive binding studies with (3)H-Pittsburgh compound B in the frontal cortices of Alzheimer's disease brains revealed high- and low-affinity binding sites for BTA-1 (Ki: 0.2 nM, 70 nM), florbetapir (1.8 nM, 53 nM) and florbetaben (1.0 nM, 65 nM). BF-227 displaced 83% of (3)H-Pittsburgh compound B binding, mainly at a low-affinity site (311 nM), whereas FDDNP only partly displaced (40%). We propose a multiple binding site model for the amyloid tracers (binding sites 1, 2 and 3), where AV-45 (florbetapir), AV-1 (florbetaben), and Pittsburgh compound B, all show nanomolar affinity for the high-affinity site (binding site 1), as visualized by positron emission tomography. BF-227 shows mainly binding to site 3 and FDDNP shows only some binding to site 2. Different amyloid tracers may provide new insight into the pathophysiological mechanisms in the progression of Alzheimer's disease.
ESTHER : Ni_2013_Brain_136_2217
PubMedSearch : Ni_2013_Brain_136_2217
PubMedID: 23757761

Title : (3)H-deprenyl and (3)H-PIB autoradiography show different laminar distributions of astroglia and fibrillar beta-amyloid in Alzheimer brain - Marutle_2013_J.Neuroinflammation_10_90
Author(s) : Marutle A , Gillberg PG , Bergfors A , Yu W , Ni R , Nennesmo I , Voytenko L , Nordberg A
Ref : J Neuroinflammation , 10 :90 , 2013
Abstract : BACKGROUND: The pathological features in Alzheimer's disease (AD) brain include the accumulation and deposition of beta-amyloid (Abeta), activation of astrocytes and microglia and disruption of cholinergic neurotransmission. Since the topographical characteristics of these different pathological processes in AD brain and how these relate to each other is not clear, this motivated further exploration using binding studies in postmortem brain with molecular imaging tracers. This information could aid the development of specific biomarkers to accurately chart disease progression.
RESULTS: In vitro binding assays demonstrated increased [(3)H]-PIB (fibrillar Abeta) and [(3)H]-PK11195 (activated microglia) binding in the frontal cortex (FC) and hippocampus (HIP), as well as increased binding of [(3)H]-L-deprenyl (activated astrocytes) in the HIP, but a decreased [(3)H]-nicotine (alpha4beta2 nicotinic acetylcholine receptor (nAChR)) binding in the FC of AD cases compared to age-matched controls. Quantitative autoradiography binding studies were also performed to investigate the regional laminar distributions of [(3)H]-L-deprenyl, [(3)H]-PIB as well as [(1)(2)(5)I]-alpha-bungarotoxin (alpha7 nAChRs) and [(3)H]-nicotine in hemisphere brain of a typical AD case. A clear lamination pattern was observed with high [(3)H]-PIB binding in all layers and [(3)H]-deprenyl in superficial layers of the FC. In contrast, [(3)H]-PIB showed low binding to fibrillar Abeta, but [(3)H]-deprenyl high binding to activated astrocytes throughout the HIP. The [(3)H]-PIB binding was also low and the [(3)H]-deprenyl binding high in all layers of the medial temporal gyrus and insular cortex in comparison to the frontal cortex. Low [(3)H]-nicotine binding was observed in all layers of the frontal cortex in comparison to layers in the medial temporal gyrus, insular cortex and hippocampus. Immunohistochemical detection in the AD case revealed abundant glial fibrillary acidic protein positive (GFAP+) reactive astrocytes and alpha7 nAChR expressing GFAP+ astrocytes both in the vicinity and surrounding Abeta neuritic plaques in the FC and HIP. Although fewer Abeta plaques were observed in the HIP, some hippocampal GFAP+ astrocytes contained Abeta-positive (6 F/3D) granules within their somata.
CONCLUSIONS: Astrocytosis shows a distinct regional pattern in AD brain compared to fibrillar Abeta, suggesting that different types of astrocytes may be associated with the pathophysiological processes in AD.
ESTHER : Marutle_2013_J.Neuroinflammation_10_90
PubMedSearch : Marutle_2013_J.Neuroinflammation_10_90
PubMedID: 23880036

Title : Apolipoprotein epsilon4 modulates phenotype of butyrylcholinesterase in CSF of patients with Alzheimer's disease - Darreh-Shori_2012_J.Alzheimers.Dis_28_443
Author(s) : Darreh-Shori T , Siawesh M , Mousavi M , Andreasen N , Nordberg A
Ref : J Alzheimers Dis , 28 :443 , 2012
Abstract : Butyrylcholinesterase K (BCHE-K) is associated with increased risk of developing Alzheimer's disease (AD) in apolipoprotein epsilon (APOE4) carriers, while among APOE4 non-carriers BCHE-K appears to be protective. Nonetheless, pure pharmacogenetic reports have provided conflicting results. To provide insights about these controversies, we combined BCHE-K pharmacogenetic observations in AD patients (n = 179) with proteomic and enzymatic analysis of plasma, cerebrospinal fluid (CSF), or both samples. We found that BCHE-K genotype was overrepresented among the AD patients (chi(2) = 14.21, p < 0.0001). Plasma BuChE activity was gene dose-dependently 20-50% less among K-carriers (p < 0.001). CSF BuChE activity did not show such robust K-gene dosage-dependency, because K homozygotes (n = 9) had 30-40% less activity compared to both non-carriers (n = 78, p < 0.01) and heterozygotes (n = 42, p < 0.09). CSF ApoE protein expression was also altered by presence of K-allele (p < 0.001, n = 129). Mutually, APOE4 altered phenotypic display of BuChE variants in CSF (p < 0.01, n = 129). In absence of APOE4, CSF BuChE activity was essentially indistinguishable among K-carriers (n = 16) and non-carriers (n = 17, p < 0.8) although the K-carriers had 24-39% less circulating BuChE protein. In contrast in presence of APOE4, the K-carriers (n = 35) had K allele dose-dependently a BuChE phenotype with 14-46% reduced activity compared to K non-carriers (p < 0.001, n = 59), despite an essentially identical BChE concentration in CSF (1 +/- 4%, p < 0.8). Pattern of the patients' cognitive performance in MMSE closely resembled the APOE4-derived phenotypic display of BuChE variants. APOE4-dependent outcome of BCHE-K genotype as AD risk factor arises through a differential phenotypic modulation of BuChE. Future pharmacogenetic studies should include assessment of the subjects' true phenotypic display of BuChE.
ESTHER : Darreh-Shori_2012_J.Alzheimers.Dis_28_443
PubMedSearch : Darreh-Shori_2012_J.Alzheimers.Dis_28_443
PubMedID: 22012848

Title : Differential levels of apolipoprotein E and butyrylcholinesterase show strong association with pathological signs of Alzheimer's disease in the brain in vivo - Darreh-Shori_2011_Neurobiol.Aging_32_2320 e15
Author(s) : Darreh-Shori T , Forsberg A , Modiri N , Andreasen N , Blennow K , Kamil C , Ahmed H , Almkvist O , Langstrom B , Nordberg A
Ref : Neurobiology of Aging , 32 :2320 e15 , 2011
Abstract : Recently, we reported that 3 of the known risk factors of Alzheimer's disease (AD), i.e., advanced age, apolipoprotein E (ApoE) epsilon4, and female gender, are associated with differential levels of ApoE proteins and butyrylcholinesterase (BuChE) in the cerebrospinal fluid (CSF) of AD patients. The ApoE epsilon4 allele and certain BuChE polymorphisms synergistically affect the conversion rate of mild cognitive impairment (MCI) to AD. Here, we investigated interrelationships between ApoE and BuChE levels, and pathological markers of AD in vivo. CSF from patients with probable AD, assessed for cerebral glucose metabolism (CMRglc; n = 50) and Pittsburgh compound B (PIB) retention (beta-amyloid [Abeta] load, n = 29) by positron emission tomography (PET), was used for measurement of BuChE, ApoE, Abeta, tau, phosphorylated tau (P-tau) and interleukin-1beta (IL-1beta) levels. Levels of ApoE and BuChE strongly correlated with CMRglc (fluorodeoxyglucose [FDG]-PET, r = 0.54, p < 0.0001, n = 50), cerebral Abeta load (PIB retention, r = 0.73, p < 0.0001, n = 29), and CSF P-tau (r = 0.73, p < 0.0001, n = 33). High ApoE protein was tied to low CMRglc and high PIB retention and P-tau. BuChE levels had opposite relationships. Other CSF covariates were levels of interleukin-1beta and Abeta(42) peptide. The pattern of the patients' cognitive Z-scores strongly supported these observations. High ApoE protein was also linked to changes in 3 of the biodynamic properties of BuChE. In vitro analysis indicated that high ApoE protein levels were related to an increased pool of dormant BuChE molecules with an abnormally high intrinsic catalytic rate in CSF, which was "turned on" by excess Abeta peptides. The findings suggest that abnormally high levels of ApoE may play a causative role in the pathological events of AD, particularly those involving the early cholinergic deficit in the AD brain, through modulation of cholinesterases activities, hence disturbing the acetylcholine-dependent activity of neurons and nonexcitable cells such as glial cells.
ESTHER : Darreh-Shori_2011_Neurobiol.Aging_32_2320 e15
PubMedSearch : Darreh-Shori_2011_Neurobiol.Aging_32_2320 e15
PubMedID: 20538374

Title : The apolipoprotein E epsilon4 allele plays pathological roles in AD through high protein expression and interaction with butyrylcholinesterase - Darreh-Shori_2011_Neurobiol.Aging_32_1236
Author(s) : Darreh-Shori T , Modiri N , Blennow K , Baza S , Kamil C , Ahmed H , Andreasen N , Nordberg A
Ref : Neurobiology of Aging , 32 :1236 , 2011
Abstract : The apolipoprotein E (ApoE) epsilon4 allele has consistently been established as an Alzheimer's disease (AD) risk factor, but its pathological contribution to AD is obscure. Certain butyrylcholinesterase (BuChE) polymorphisms together with the ApoE epsilon4 allele synergistically increase the risk of AD. In addition, AD risk factors, i.e. advanced age, female gender and ApoE epsilon4 are associated with different levels of CSF BuChE in AD patients, and BuChE protein attenuates Abeta fibrillization in vitro. Here we investigated the roles of ApoE and BuChE gene products as modulators of pathological features of AD in vivo. We found that AD risk factors were associated with different levels of ApoE protein in the CSF of AD patients (n=115). Women and ApoE epsilon4 carriers had the highest levels of ApoE protein (up by 50-120%, p<0.01-0.0001), which were increased with age (r=0.30, p<0.0006). The CSF surrogate markers of pathological features of AD, i.e. high tau and P-tau, low Abeta(42) and high tau/Abeta(42) ratio, were associated with high levels of ApoE protein. Intriguingly, high ApoE protein levels were not only associated with low amounts of BuChE, but they also altered the aging and activity of this enzyme in concentration- and isoform-dependent manners, particularly in the presence of Abeta peptides. Both ApoE and BuChE levels were also differentially related to levels of the proinflammatory cytokine IL-1beta. In conclusion, ApoE epsilon4 might impart its pathological role through high protein expression and interaction with BuChE, which in turn might modulate central cholinergic activity and Abeta load in the brain.
ESTHER : Darreh-Shori_2011_Neurobiol.Aging_32_1236
PubMedSearch : Darreh-Shori_2011_Neurobiol.Aging_32_1236
PubMedID: 19713000

Title : Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer's disease - Kadir_2011_Brain_134_301
Author(s) : Kadir A , Marutle A , Gonzalez D , Scholl M , Almkvist O , Mousavi M , Mustafiz T , Darreh-Shori T , Nennesmo I , Nordberg A
Ref : Brain , 134 :301 , 2011
Abstract : The accumulation of beta-amyloid in the brain is an early event in Alzheimer's disease. This study presents the first patient with Alzheimer's disease who underwent positron emission tomography imaging with the amyloid tracer, Pittsburgh Compound B to visualize fibrillar beta-amyloid in the brain. Here we relate the clinical progression, amyloid and functional brain positron emission tomography imaging with molecular neuropathological alterations at autopsy to gain new insight into the relationship between beta-amyloid accumulation, inflammatory processes and the cholinergic neurotransmitter system in Alzheimer's disease brain. The patient underwent positron emission tomography studies with (18)F-fluorodeoxyglucose three times (at ages 53, 56 and 58 years) and twice with Pittsburgh Compound B (at ages 56 and 58 years), prior to death at 61 years of age. The patient showed a pronounced decline in cerebral glucose metabolism and cognition during disease progression, while Pittsburgh Compound B retention remained high and stable at follow-up. Neuropathological examination of the brain at autopsy confirmed the clinical diagnosis of pure Alzheimer's disease. A comprehensive neuropathological investigation was performed in nine brain regions to measure the regional distribution of beta-amyloid, neurofibrillary tangles and the levels of binding of (3)H-nicotine and (125)I-alpha-bungarotoxin to neuronal nicotinic acetylcholine receptor subtypes, (3)H-L-deprenyl to activated astrocytes and (3)H-PK11195 to microglia, as well as butyrylcholinesterase activity. Regional in vivo (11)C-Pittsburgh Compound B-positron emission tomography retention positively correlated with (3)H-Pittsburgh Compound B binding, total insoluble beta-amyloid, and beta-amyloid plaque distribution, but not with the number of neurofibrillary tangles measured at autopsy. There was a negative correlation between regional fibrillar beta-amyloid and levels of (3)H-nicotine binding. In addition, a positive correlation was found between regional (11)C-Pittsburgh Compound B positron emission tomography retention and (3)H-Pittsburgh Compound B binding with the number of glial fibrillary acidic protein immunoreactive cells, but not with (3)H-L-deprenyl and (3)H-PK-11195 binding. In summary, high (11)C-Pittsburgh Compound B positron emission tomography retention significantly correlates with both fibrillar beta-amyloid and losses of neuronal nicotinic acetylcholine receptor subtypes at autopsy, suggesting a closer involvement of beta-amyloid pathology with neuronal nicotinic acetylcholine receptor subtypes than with inflammatory processes.
ESTHER : Kadir_2011_Brain_134_301
PubMedSearch : Kadir_2011_Brain_134_301
PubMedID: 21149866

Title : Pittsburgh compound-B and Alzheimer's disease biomarkers in CSF, plasma and urine: An exploratory study - Degerman_2010_Dement.Geriatr.Cogn.Disord_29_204
Author(s) : Degerman Gunnarsson M , Lindau M , Wall A , Blennow K , Darreh-Shori T , Basu S , Nordberg A , Larsson A , Lannfelt L , Basun H , Kilander L
Ref : Dementia & Geriatric Cognitive Disorders , 29 :204 , 2010
Abstract : BACKGROUND: The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PIB) is an in vivo ligand for measuring beta-amyloid (Abeta) load. Associations between PET PIB and cerebrospinal fluid (CSF) Abeta1-42 and apolipoprotein E epsilon4 (APOE epsilon4) have been observed in several studies, but the relations between PIB uptake and other biomarkers of Alzheimer's disease (AD) are less investigated. METHOD: PET PIB, PET 18Fluoro-2-deoxy-D-glucose and different AD biomarkers were measured twice in CSF, plasma and urine 12 months apart in 10 patients with a clinical diagnosis of mild to moderate AD.
RESULTS: PIB retention was constant over 1 year, inversely related to low CSF Abeta1-42 (p = 0.01) and correlated positively to the numbers of the APOE epsilon4 allele (0, 1 or 2) (p = 0.02). There was a relation between mean PIB retention and CSF ApoE protein (r = -0.59, p = 0.07), and plasma cystatin C (r = -0.56, p = 0.09). CONCLUSION: PIB retention is strongly related to CSF Abeta1-42, and to the numbers of the APOE epsilon4 allele.
ESTHER : Degerman_2010_Dement.Geriatr.Cogn.Disord_29_204
PubMedSearch : Degerman_2010_Dement.Geriatr.Cogn.Disord_29_204
PubMedID: 20332638

Title : Effect of huprine X on beta-amyloid, synaptophysin and alpha7 neuronal nicotinic acetylcholine receptors in the brain of 3xTg-AD and APPswe transgenic mice - Hedberg_2010_Neurodegener.Dis_7_379
Author(s) : Hedberg MM , Clos MV , Ratia M , Gonzalez D , Lithner CU , Camps P , Munoz-Torrero D , Badia A , Gimenez-Llort L , Nordberg A
Ref : Neurodegener Dis , 7 :379 , 2010
Abstract : BACKGROUND: Several studies implicate acetylcholinesterase (AChE) in the pathogenesis of Alzheimer's disease (AD), raising the question of whether inhibitors of AChE also might act in a disease-modifying manner. Huprine X (HX), a reversible AChE inhibitor hybrid of tacrine and huperzine A, has shown to affect the amyloidogenic process in vitro. In this study, the aim was to investigate whether HX could affect the AD-related neuropathology in vivo in two mouse models. METHODS: Tg2576 (K670M/N671L) (APPswe) and 3xTg-AD (K670M/N671L, PS1M146V, tauP301L) mice were treated with HX (0.12 mumol/kg, i.p., 21 days) or saline at 6-7 months. Human beta-amyloid (Abeta) was measured by ELISA, synaptophysin by Western blot and alpha7 neuronal nicotinic acetylcholine receptors (nAChRs) were analyzed by [(125)I]alpha-bungarotoxin autoradiography. RESULTS: Treatment with HX reduced insoluble Abeta1-40 (about 40%) in the hippocampus of 3xTg-AD mice, while showing no effect in APPswe mice. Additionally, HX markedly increased cortical synaptophysin levels (about 140%) and decreased (about 30%) the levels of alpha7 nAChRs in the caudate nucleus of 3xTg-AD mice, while increasing (about 10%) hippocampal alpha7 nAChRs in APPswe mice. CONCLUSION: The two mouse models react differently to HX treatment, possibly due to their differences in brain neuropathology. The modulation of Abeta and synaptophysin by HX in 3xTg-AD mice might be due to its suggested interaction with the peripheral anionic site on AChE, and/or via cholinergic mechanisms involving activation of cholinergic receptors. Our results provide further evidence that drugs targeting AChE affect some of the fundamental processes that contribute to neurodegeneration, but whether HX might act in a disease-modifying manner in AD patients remains to be proven.
ESTHER : Hedberg_2010_Neurodegener.Dis_7_379
PubMedSearch : Hedberg_2010_Neurodegener.Dis_7_379
PubMedID: 20689242

Title : Different cholinesterase inhibitor effects on CSF cholinesterases in Alzheimer patients - Nordberg_2009_Curr.Alzheimer.Res_6_4
Author(s) : Nordberg A , Darreh-Shori T , Peskind E , Soininen H , Mousavi M , Eagle G , Lane R
Ref : Curr Alzheimer Res , 6 :4 , 2009
Abstract : BACKGROUND: The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities and protein levels, in the cerebrospinal fluid (CSF) of Alzheimer disease (AD) patients.
METHODS AND FINDINGS: AD patients aged 50-85 years were randomized to open-label treatment with oral rivastigmine, donepezil or galantamine for 13 weeks. AChE and BuChE activities were assayed by Ellman's colorimetric method. Protein levels were assessed by enzyme-linked immunosorbent assay (ELISA). Primary analyses were based on the Completer population (randomized patients who completed Week 13 assessments). 63 patients were randomized to treatment. Rivastigmine was associated with decreased AChE activity by 42.6% and decreased AChE protein levels by 9.3%, and decreased BuChE activity by 45.6% and decreased BuChE protein levels by 21.8%. Galantamine decreased AChE activity by 2.1% and BuChE activity by 0.5%, but increased AChE protein levels by 51.2% and BuChE protein levels by 10.5%. Donepezil increased AChE and BuChE activities by 11.8% and 2.8%, respectively. Donepezil caused a 215.2% increase in AChE and 0.4% increase in BuChE protein levels. Changes in mean AChE-Readthrough/Synaptic ratios, which might reflect underlying neurodegenerative processes, were 1.4, 0.6, and 0.4 for rivastigmine, donepezil and galantamine, respectively.
CONCLUSION: The findings suggest pharmacologically-induced differences between rivastigmine, donepezil and galantamine. Rivastigmine provides sustained inhibition of AChE and BuChE, while donepezil and galantamine do not inhibit BuChE and are associated with increases in CSF AChE protein levels. The clinical implications require evaluation.
ESTHER : Nordberg_2009_Curr.Alzheimer.Res_6_4
PubMedSearch : Nordberg_2009_Curr.Alzheimer.Res_6_4
PubMedID: 19199870

Title : Safety of lumbar puncture procedures in patients with Alzheimer's disease - Peskind_2009_Curr.Alzheimer.Res_6_290
Author(s) : Peskind E , Nordberg A , Darreh-Shori T , Soininen H
Ref : Curr Alzheimer Res , 6 :290 , 2009
Abstract : Changes in cerebrospinal fluid (CSF) biomarkers are representative of biochemical changes in the brain. Collection of CSF by lumbar puncture (LP) is essential for biomarker analysis, which is important for research in neurodegenerative disorders. However, LP for research purposes has been controversial due to a reported high incidence of severe LP headache when using standard 18g or 20g Quincke needles with a beveled cutting tip. A procedural safety analysis was performed using the database of a multicenter, 13-week study of CSF cholinesterase activity. A 24g Sprotte atraumatic needle was used to collect CSF at baseline and at Week 13 from 63 older patients with mild to moderate Alzheimer's disease. There was a < 2% LP headache incidence, and a favorable safety profile was reported. In conclusion, LP performed with a 24g Sprotte atraumatic needle (blunt, "bullet" tip) was a well tolerated procedure, with good acceptability.
ESTHER : Peskind_2009_Curr.Alzheimer.Res_6_290
PubMedSearch : Peskind_2009_Curr.Alzheimer.Res_6_290
PubMedID: 19519311

Title : Synergistic effect of apolipoprotein E epsilon4 and butyrylcholinesterase K-variant on progression from mild cognitive impairment to Alzheimer's disease - Lane_2008_Pharmacogenet.Genomics_18_289
Author(s) : Lane R , Feldman HH , Meyer J , He Y , Ferris SH , Nordberg A , Darreh-Shori T , Soininen H , Pirttila T , Farlow MR , Sfikas N , Ballard C , Greig NH
Ref : Pharmacogenet Genomics , 18 :289 , 2008
Abstract : OBJECTIVE: To evaluate the synergistic effects of the apolipoprotein E (APOE) epsilon4 and butyrylcholinesterase K-variant (BCHE-K) alleles on progression to Alzheimer's disease (AD) in individuals with mild cognitive impairment (MCI).
METHODS: This was a post-hoc exploratory analysis from a 3-4-year, randomized, placebo-controlled study of rivastigmine in participants with MCI (InDDEx study). Participants who consented to genetic testing were included in the current analyses. The incidence of progression to AD, cognitive decline and changes in MRI brain volumes were investigated in participants from the placebo arm of the InDDEx study.
RESULTS: Of the 1018 participants in the overall study, 464 were successfully genotyped for both APOE and butyrylcholinesterase. Of these, 68 (14.7%) carried > or =1 APOE epsilon4 and > or =1 BCHE-K allele. The presence of APOE epsilon4 was associated with a significantly higher incidence of progression to AD whereas the presence of BCHE-K had no independent effect on progression. A synergistic effect of the combined presence of APOE epsilon4 and BCHE-K on the time to clinical diagnosis of AD and on MRI brain volumes was seen. Progression to AD and hippocampal volumetric loss was greatest in participants who carried both APOE epsilon4 and BCHE-K alleles and lowest in BCHE-K carriers without the APOE epsilon4 allele. CONCLUSION: In MCI, the risk of cognitive decline, hippocampal volumetric loss and progression to AD seems to be the greatest in individuals who carry at least one copy of both the BCHE-K and APOE epsilon4 alleles.
ESTHER : Lane_2008_Pharmacogenet.Genomics_18_289
PubMedSearch : Lane_2008_Pharmacogenet.Genomics_18_289
PubMedID: 18334913

Title : PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD - Kadir_2008_Neurobiol.Aging_29_1204
Author(s) : Kadir A , Darreh-Shori T , Almkvist O , Wall A , Grut M , Strandberg B , Ringheim A , Eriksson B , Blomquist G , Langstrom B , Nordberg A
Ref : Neurobiology of Aging , 29 :1204 , 2008
Abstract : The effect of galantamine treatment on cortical acetylcholinesterase (AChE) activity and nicotinic receptor binding was investigated by positron emission tomography (PET) in 18 patients with mild Alzheimer's disease (AD) in relation to galantamine concentration and the patients' cognitive performances. The first 3 months of the study was of a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24mg/day) and 6 patients the placebo, and this was followed by 9 months' galantamine treatment in all patients. The patients underwent PET examinations to measure cortical AChE activity ((11)C-PMP) and (11)C-nicotine binding. Neuropsychological tests were performed throughout the study. Inhibition (30-40%) of cortical AChE activity was observed after 3 weeks to 12 months of galantamine treatment. No significant change in mean cortical (11)C-nicotine binding was observed during the study. (11)C-Nicotine binding, however, positively correlated with plasma galantamine concentration. Both the changes of AChE activity and (11)C-nicotine binding correlated positively with the results of a cognitive test of attention. In conclusion, galantamine caused sustained AChE inhibition for up to 12 months. At the individual level, the in vivo cortical AChE inhibition and (11)C-nicotine binding were associated with changes in the attention domain of cognition rather than episodic memory.
ESTHER : Kadir_2008_Neurobiol.Aging_29_1204
PubMedSearch : Kadir_2008_Neurobiol.Aging_29_1204
PubMedID: 17379359

Title : Transgenic mice overexpressing human acetylcholinesterase and the Swedish amyloid precursor protein mutation: effect of nicotine treatment - Hedberg_2008_Neurosci_152_223
Author(s) : Hedberg MM , Svedberg MM , Mustafiz T , Yu WF , Mousavi M , Guan ZZ , Unger C , Nordberg A
Ref : Neuroscience , 152 :223 , 2008
Abstract : Acetylcholinesterase (AChE) is shown to promote deposition of beta-amyloid (Abeta) peptides and to enhance Abeta toxicity. Tg2576 (transgenic mice carrying the Swedish mutation of amyloid precursor protein, APPswe) mice and mice overexpressing human synaptic acetylcholinesterase (AChE-S) were crossed (hAChE-Tg//APPswe), to study the effects of brain Abeta, from 1 to 10 months of age, under the constant influence of AChE-S. The effect of nicotine treatment was also evaluated in these mice since we have previously shown that nicotine dramatically decreases Abeta levels in single transgenic APPswe mice. Already at 1 and 3 months, hAChE-Tg// APPswe mice showed increased levels of cortical insoluble Abeta1-40 and Abeta1-42 compared with APPswe mice, whereas APPswe mice displayed increased soluble Abeta1-40. Abeta plaques were detected at 7 months, thus before onset of plaque formation in APPswe mice. No differences were found in [125I]alpha-bungarotoxin binding sites or hippocampal glial fibrillary acidic protein (GFAP) immunoreactivity between hAChE-Tg//APPswe, and APPswe mice at either 1 or 10 months of age. L(-)-Nicotine (final dose 0.45 mg/kg) treatment twice daily for 10 days to 14-month-old hAChE-Tg// APPswe mice increased cortical insoluble Abeta1-40 levels, while both L(-)- and D(+)-nicotine (final dose 0.45 mg/kg) increased soluble Abeta1-42. L(-)-Nicotine reduced hippocampal GFAP immunoreactivity both in hAChE-Tg//APPswe mice and non-transgenic controls, while D(+)-nicotine caused a decrease only in hAChE-Tg//APPswe mice. Moreover, D(+)-nicotine increased the [125I]alpha-bungarotoxin binding sites in the hippocampus, and cortex of the hAChE-Tg//APPswe mice. In conclusion, already at a very young age, hAChE-Tg// APPswe mice exhibit increased levels of aggregated Abeta compared with APPswe mice, due to the possible interaction between Abeta and AChE-S, whereas APPswe mice exhibit increased soluble Abeta. The interaction between Abeta and AChE-S may also explain the different effect of nicotine on Abeta pathology in the hAChE-Tg//APPswe mice. The results in this study emphasize the importance of using different transgenic mouse models for evaluating the effect of new drug candidates for the treatment of Alzheimer's disease.
ESTHER : Hedberg_2008_Neurosci_152_223
PubMedSearch : Hedberg_2008_Neurosci_152_223
PubMedID: 18164554

Title : Inhibition of acetylcholinesterase in CSF versus brain assessed by 11C-PMP PET in AD patients treated with galantamine - Darreh-Shori_2008_Neurobiol.Aging_29_168
Author(s) : Darreh-Shori T , Kadir A , Almkvist O , Grut M , Wall A , Blomquist G , Eriksson B , Langstrom B , Nordberg A
Ref : Neurobiology of Aging , 29 :168 , 2008
Abstract : The relationship between acetylcholinesterase (AChE) activity in the CSF and brain of patients with Alzheimer's disease (AD) was investigated in 18 mild AD patients following galantamine treatment. The first 3 months of the study had a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24 mg/day) and six patients placebo. This was followed by 9 months galantamine treatment in all patients. Activities and protein levels of both the "read-through" AChE (AChE-R) and the synaptic (AChE-S) variants in CSF were assessed in parallel together with the regional brain AChE activity by (11)C-PMP and PET. The AChE-S inhibition was 30-36% in CSF, which correlated well with the in vivo AChE inhibition in the brain. No significant AChE inhibition was observed in the placebo group. The increased level of the AChE-R protein was 16% higher than that of AChE-S. Both the AChE inhibition and the increased level of AChE-R protein positively correlated with the patient's performance in cognitive tests associated with visuospatial ability and attention. In conclusion, AChE levels in CSF closely mirror in vivo brain AChE levels prior to and after treatment with the cholinesterase inhibitors. A positive cognitive response seems to dependent on the AChE inhibition level, which is balanced by an increased protein level of the AChE-R variant in the patients.
ESTHER : Darreh-Shori_2008_Neurobiol.Aging_29_168
PubMedSearch : Darreh-Shori_2008_Neurobiol.Aging_29_168
PubMedID: 17196712

Title : Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine - Marutle_2007_Proc.Natl.Acad.Sci.U.S.A_104_12506
Author(s) : Marutle A , Ohmitsu M , Nilbratt M , Greig NH , Nordberg A , Sugaya K
Ref : Proc Natl Acad Sci U S A , 104 :12506 , 2007
Abstract : In a previous study, we found that human neural stem cells (HNSCs) exposed to high concentrations of secreted amyloid-precursor protein (sAPP) in vitro differentiated into mainly astrocytes, suggesting that pathological alterations in APP processing during neurodegenerative conditions such as Alzheimer's disease (AD) may prevent neuronal differentiation of HNSCs. Thus, successful neuroplacement therapy for AD may require regulating APP expression to favorable levels to enhance neuronal differentiation of HNSCs. Phenserine, a recently developed cholinesterase inhibitor (ChEI), has been reported to reduce APP levels in vitro and in vivo. In this study, we found reductions of APP and glial fibrillary acidic protein (GFAP) levels in the hippocampus of APP23 mice after 14 days treatment with (+)-phenserine (25 mg/kg) lacking ChEI activity. No significant change in APP gene expression was detected, suggesting that (+)-phenserine decreases APP levels and reactive astrocytes by posttranscription regulation. HNSCs transplanted into (+)-phenserine-treated APP23 mice followed by an additional 7 days of treatment with (+)-phenserine migrated and differentiated into neurons in the hippocampus and cortex after 6 weeks. Moreover, (+)-phenserine significantly increased neuronal differentiation of implanted HNSCs in hippocampal and cortical regions of APP23 mice and in the CA1 region of control mice. These results indicate that (+)-phenserine reduces APP protein in vivo and increases neuronal differentiation of HNSCs. Combination use of HNSC transplantation and treatment with drugs such as (+)-phenserine that modulate APP levels in the brain may be a useful tool for understanding mechanisms regulating stem cell migration and differentiation during neurodegenerative conditions in AD.
ESTHER : Marutle_2007_Proc.Natl.Acad.Sci.U.S.A_104_12506
PubMedSearch : Marutle_2007_Proc.Natl.Acad.Sci.U.S.A_104_12506
PubMedID: 17640880

Title : Effects of statins on alpha7 nicotinic receptor, cholinesterase and alpha-form of secreted amyloid precursor peptide in SH-SY5Y cells - Roensch_2007_Neurochem.Int_50_800
Author(s) : Roensch J , Crisby M , Nordberg A , Xiao Y , Zhang LJ , Guan ZZ
Ref : Neurochem Int , 50 :800 , 2007
Abstract : In order to reveal the neuroprotective effects of statins that could be of interest for the prevention and treatment of Alzheimer's disease (AD), we investigated the expression of nicotinic acetylcholine receptors (nAChRs) detected by RT-PCR, the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by colorimetric determination, and the levels of the alpha-form of secreted beta-amyloid precursor protein (alphaAPPs) by Western blotting in neuroblastoma (SH-SY5Y) cells exposed to lovastatin, atorvastatin, rosuvastatin and simvastatin, respectively. The results indicated that all statins studied, both lipophilic and hydrophilic, induced high expression of alpha7 nAChR, decreased cholinesterase activities, and increased alphaAPPs, which suggests that statins might play important neuroprotective roles in AD treatment.
ESTHER : Roensch_2007_Neurochem.Int_50_800
PubMedSearch : Roensch_2007_Neurochem.Int_50_800
PubMedID: 17412455

Title : Changes in brain 11C-nicotine binding sites in patients with mild Alzheimer's disease following rivastigmine treatment as assessed by PET - Kadir_2007_Psychopharmacology.(Berl)_191_1005
Author(s) : Kadir A , Darreh-Shori T , Almkvist O , Wall A , Langstrom B , Nordberg A
Ref : Psychopharmacology (Berl) , 191 :1005 , 2007
Abstract : RATIONALE: Marked reduction in the cortical nicotinic acetylcholine receptors is observed in the brain of patients suffering from Alzheimer's disease (AD). Although cholinesterase inhibitors are used for symptomatic treatment of mild to moderate AD patients, numerous long-term treatment studies indicate that they might stabilize or halt the progression of the disease by restoring the central cholinergic neurotransmission. Thus, we used positron emission tomography (PET) technique as a sensitive approach to assess longitudinal changes in the nicotine binding sites in the brains of patients with AD. OBJECTIVE: To evaluate changes in brain nicotinic binding sites in relation to inhibition level of cholinesterases in cerebrospinal fluid (CSF) and plasma and changes in cognitive performance of the patients in different neuropsychological tests after rivastigmine treatment. MATERIALS AND METHODS: Ten mild AD patients received rivastigmine for 12 months. A dual-tracer PET model with administration of (15)O-water and (S)(-)(11)C-nicotine was used to assess (11)C-nicotine binding sites in the brain at baseline and after 3 and 12 months of the treatment. Cholinesterase activities in CSF and plasma were assessed colorimetrically. RESULTS: The (11)C-nicotine binding sites were significantly increased 12-19% in several cortical brain regions after 3 months compared with baseline, while the increase was not significant after 12 months of the treatment. After 3 months treatment, low enzyme inhibition in CSF and plasma was correlated with higher cortical (11)C-nicotine binding. The (11)C-nicotine binding positively correlated with attentional task at the 12-month follow-up. CONCLUSION: Changes in the (11)C-nicotine binding during rivastigmine treatment might represent remodeling of the cholinergic and related neuronal network.
ESTHER : Kadir_2007_Psychopharmacology.(Berl)_191_1005
PubMedSearch : Kadir_2007_Psychopharmacology.(Berl)_191_1005
PubMedID: 17310387

Title : Two-year follow-up of amyloid deposition in patients with Alzheimer's disease - Engler_2006_Brain_129_2856
Author(s) : Engler H , Forsberg A , Almkvist O , Blomquist G , Larsson E , Savitcheva I , Wall A , Ringheim A , Langstrom B , Nordberg A
Ref : Brain , 129 :2856 , 2006
Abstract : Beta amyloid is one of the major histopathological hallmarks of Alzheimer's disease. We recently reported in vivo imaging of amyloid in 16 Alzheimer patients, using the PET ligand N-methyl[11C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole (PIB). In the present study we rescanned these 16 Alzheimer patients after 2.0 +/- 0.5 years and have described the interval change in amyloid deposition and regional cerebral metabolic rate for glucose (rCMRGlc) at follow-up. Sixteen patients with Alzheimer's disease were re-examined by means of PET, using PIB and 2-[18F]fluoro-2-deoxy-d-glucose (FDG) after 2.0 +/- 0.5 years. The patients were all on cholinesterase inhibitor treatment and five also on treatment with the N-methyl-d-aspartate (NMDA) antagonist memantine. In order to estimate the accuracy of the PET PIB measurements, four additional Alzheimer patients underwent repeated examinations with PIB within 20 days (test-retest). Relative PIB retention in cortical regions differed by 3-7% in the test-retest study. No significant difference in PIB retention was observed between baseline and follow-up while a significant (P < 0.01) 20% decrease in rCMRGlc was observed in cortical brain regions. A significant negative correlation between rCMRGlc and PIB retention was observed in the parietal cortex in the Alzheimer patients at follow-up (r = 0.67, P = 0.009). A non-significant decline in Mini-Mental State Examination (MMSE) score from 24.3 +/- 3.7 (mean +/- standard deviation) to 22.7 +/- 6.1 was measured at follow-up. Five of the Alzheimer patients showed a significant decline in MMSE score of >3 (21.4 +/- 3.5 to 15.6 +/- 3.9, P < 0.01) (AD-progressive) while the rest of the patients were cognitively more stable (MMSE score = 25.6 +/- 3.1 to 25.9 +/- 3.7) (AD-stable) compared with baseline. A positive correlation (P = 0.001) was observed in the parietal cortex between Rey Auditory Verbal Learning (RAVL) test score and rCMRGlc at follow-up while a negative correlation (P = 0.018) was observed between RAVL test and PIB retention in the parietal at follow-up. Relatively stable PIB retention after 2 years of follow-up in patients with mild Alzheimer's disease suggests that amyloid deposition in the brain reaches a plateau by the early clinical stages of Alzheimer's disease and therefore may precede a decline in rCMRGlc and cognition. It appears that anti-amyloid therapies will need to induce a significant decrease in amyloid load in order for PIB PET images to detect a drug effect in Alzheimer patients. FDG imaging may be able to detect a stabilization of cerebral metabolism caused by therapy administered to patients with a clinical diagnosis of Alzheimer's disease.
ESTHER : Engler_2006_Brain_129_2856
PubMedSearch : Engler_2006_Brain_129_2856
PubMedID: 16854944

Title : Longitudinal PET evaluation of cerebral glucose metabolism in rivastigmine treated patients with mild Alzheimer's disease - Stefanova_2006_J.Neural.Transm.(Vienna)_113_205
Author(s) : Stefanova E , Wall A , Almkvist O , Nilsson A , Forsberg A , Langstrom B , Nordberg A
Ref : J Neural Transm (Vienna) , 113 :205 , 2006
Abstract : In this study 11 patients with mild Alzheimer's disease (AD) were treated with the cholinesterase inhibitor rivastigmine (mean dose 8.6 +/- 1.3'mg) for 12 months and underwent positron emission tomography (PET) studies of cerebral glucose metabolism (CMRglc) and neuropsychological testing at baseline and after 12 months. An untreated group of 10 AD patients served as control group. While the untreated AD patients showed a significant decline of CMRglc in the temporo-parietal and frontal cortical regions after 12 months follow-up the rivastigmine-treated patients showed no decline in CMRglc in corresponding cortical brain regions. Furthermore, a significant dose-related increase in CMRglc was recorded in the right frontal association region after 12 months rivastigmine treatment. A positive correlation was observed between changes in CMRglc and several cognitive tests in patients receiving higher doses (10.5-12'mg) of rivastigmine. These results suggest a stabilization effect of rivastigmine on CMRglc in mild AD patients receiving long-term rivastigmine treatment.
ESTHER : Stefanova_2006_J.Neural.Transm.(Vienna)_113_205
PubMedSearch : Stefanova_2006_J.Neural.Transm.(Vienna)_113_205
PubMedID: 16049637

Title : Mechanisms behind the neuroprotective actions of cholinesterase inhibitors in Alzheimer disease - Nordberg_2006_Alzheimer.Dis.Assoc.Disord_20_S12
Author(s) : Nordberg A
Ref : Alzheimer Disease & Associated Disorders , 20 :S12 , 2006
Abstract : Inhibitors of the enzyme acetylcholinesterase (AChE) are presently used as long-term symptomatic treatments for patients with Alzheimer disease (AD), as they enhance central levels of synaptic acetylcholine. The accumulation of evidence implicating AChE in the pathogenesis of AD raises the question of whether, in addition to their palliative actions, inhibitors of this enzyme are able to act as disease-modifying agents. In addition to their catalytic effects, there is a suggestion that AChE inhibitors may influence expression of AChE isoforms and increase expression of nicotinic receptors, both of which correlate with cognitive improvements in AD patients. The neuroprotective effect of nicotine, presumably mediated via nicotinic receptors, against beta-amyloid (Abeta) toxicity and its effect on amyloid precursor protein (APP) and Abeta production has previously been established. It has also been shown that AChE inhibitors influence APP processing and attenuate Abeta-induced toxicity via mechanisms including interruption of the production of Abeta, alteration of the levels of Abeta 1-50 and 1-52, and formation of the soluble form of APP. Some of these effects seem to occur independently of nicotinic receptors, however. If such experimental in vitro observations can be extrapolated into clinical neuroprotective properties, AChE inhibitors could positively modulate the disease course of AD.
ESTHER : Nordberg_2006_Alzheimer.Dis.Assoc.Disord_20_S12
PubMedSearch : Nordberg_2006_Alzheimer.Dis.Assoc.Disord_20_S12
PubMedID: 16772751

Title : Emerging biology of the cholinergic system across the spectrum of Alzheimer's disease - Nordberg_2006_Int.Psychogeriatr_18 Suppl 1_S3
Author(s) : Nordberg A
Ref : Int Psychogeriatr , 18 Suppl 1 :S3 , 2006
Abstract : The pathological processes that lead to Alzheimer's disease (AD) begin decades before the onset of dementia. Brain abnormalities in genetically susceptible individuals have been observed even in young adults. Patients with AD differ from normal elderly patients in brain morphology and neurochemistry. Important observations include increasing appearance of amyloid plaques and neurofibrillary tangles, progressive loss of hippocampal volume, reduced cerebral glucose utilization, inflammatory processes, glial activation, and impairment of cholinergic function with losses of nicotinic acetylcholine receptors. These changes appear to begin in the asymptomatic stages and continue as cognition and then function and behavior are disrupted. Mild cognitive impairment (MCI) may be the first cognitive manifestation of this pathogenic process moderated by ongoing compensatory neurochemical mechanisms in the cholinergic system. Recent advances in positron emission tomography imaging techniques, including the development of the Pittsburgh B compound (PIB), allow in vivo visualization of amyloid plaques. These techniques have the potential to enable brain amyloid load to be monitored over time and to be related to brain function. Emerging evidence suggests that beta-amyloid may interact with nicotinic receptors. This interaction may have clinically significant downstream effects and may mediate amyloid neurotoxicity. The cholinesterase inhibitors may have multiple actions, depending on the stage of the disease, from very mild to severe.
ESTHER : Nordberg_2006_Int.Psychogeriatr_18 Suppl 1_S3
PubMedSearch : Nordberg_2006_Int.Psychogeriatr_18 Suppl 1_S3
PubMedID:

Title : Differential CSF butyrylcholinesterase levels in Alzheimer's disease patients with the ApoE epsilon4 allele, in relation to cognitive function and cerebral glucose metabolism - Darreh-Shori_2006_Neurobiol.Dis_24_326
Author(s) : Darreh-Shori T , Brimijoin S , Kadir A , Almkvist O , Nordberg A
Ref : Neurobiol Dis , 24 :326 , 2006
Abstract : Butyrylcholinesterase (BuChE) is increased in the cerebral cortex of Alzheimer's disease (AD) patients, particularly those carrying epsilon4 allele of the apolipoprotein E gene (ApoE) and certain BuChE variants that predict increased AD risk and poor response to anticholinesterase therapy. We measured BuChE activity and protein level in CSF of eighty mild AD patients in relation to age, gender, ApoE epsilon4 genotype, cognition and cerebral glucose metabolism (CMRglc). BuChE activity was 23% higher in men than women (p<0.03) and 40-60% higher in ApoE epsilon4 negative patients than in those carrying one or two epsilon4 alleles (p<0.0004). CSF BuChE level correlated with cortical CMRglc. Patients with high to moderate CSF BuChE showed better cognitive function scores than others. We hypothesize that CSF BuChE varies inversely with BuChE in cortical amyloid plaques. Thus, low BuChE in a patient's CSF may predict extensive incorporation in neuritic plaques, increased neurotoxicity and greater central neurodegeneration.
ESTHER : Darreh-Shori_2006_Neurobiol.Dis_24_326
PubMedSearch : Darreh-Shori_2006_Neurobiol.Dis_24_326
PubMedID: 16973370

Title : [Administration of symptom-relieving drugs in Alzheimer disease is beneficial] -
Author(s) : Nordberg A , Eriksdotter-Jonhagen M , Garlind A , Grut M , Freund-Levi Y , Cornelius C , Ekstrom A , Fastbom J , Sedvall M , Viitanen M
Ref : Lakartidningen , 103 :369 , 2006
PubMedID: 16536040

Title : Effect of subchronic treatment of memantine, galantamine, and nicotine in the brain of Tg2576 (APPswe) transgenic mice - Unger_2006_J.Pharmacol.Exp.Ther_317_30
Author(s) : Unger C , Svedberg MM , Yu WF , Hedberg MM , Nordberg A
Ref : Journal of Pharmacology & Experimental Therapeutics , 317 :30 , 2006
Abstract : An increasing number of studies suggest that the present clinical therapy used in Alzheimer's disease (AD), in addition to having a symptomatic effect, also may interact with the ongoing neuropathological processes in the brain. The aim of this study was to investigate the effect of the cholinesterase inhibitor galantamine and the N-methyl-d-aspartate (NMDA) antagonist memantine in comparison to nicotine on the neuropathology of Tg2576 transgenic mice (APPswe). Nontransgenic and APPswe mice at 10 months of age were treated subcutaneously with saline, memantine, galantamine, or nicotine for 10 days. Nicotine reduced the guanidinium-soluble amyloid-beta peptide (Abeta) levels by 46 to 66%, whereas the intracellular Abeta levels remained unchanged. Treatment with nicotine also resulted in less glial fibrillary acidic protein immunoreactive astrocytes around the plaques, increased levels of synaptophysin, and increased number of alpha7 nicotinic acetylcholine receptors (nAChRs) in the cortex of APPswe transgenic mice. Galantamine treatment caused an increase in the cortical levels of synaptophysin in the APPswe mice. Memantine treatment reduced the total cortical levels of membrane-bound amyloid precursor protein (45-55%) in both transgenic and nontransgenic mice, which eventually may decrease the level of Abeta. In conclusion, galantamine, memantine, and nicotine have different interactions with Abeta processes, alpha7 nAChRs, and NMDA receptors in APPswe mice. These different effects might have therapeutic relevance, and this knowledge might be applicable to the development of new effective therapeutic strategies for AD.
ESTHER : Unger_2006_J.Pharmacol.Exp.Ther_317_30
PubMedSearch : Unger_2006_J.Pharmacol.Exp.Ther_317_30
PubMedID: 16354790

Title : Changes in the activity and protein levels of CSF acetylcholinesterases in relation to cognitive function of patients with mild Alzheimer's disease following chronic donepezil treatment - Darreh-Shori_2006_J.Neural.Transm.(Vienna)_113_1791
Author(s) : Darreh-Shori T , Meurling L , Pettersson T , Hugosson K , Hellstrom-Lindahl E , Andreasen N , Minthon L , Nordberg A
Ref : J Neural Transm (Vienna) , 113 :1791 , 2006
Abstract : OBJECTIVES: To evaluate long-term changes in acetylcholinesterase (AChE) activity in CSF and blood following donepezil treatment in relation to the concentration of donepezil and cognition in AD patients.
METHODS: CSF or blood (or both) samples of a total of 104 patients with mild AD were used [MMSE score 23 +/- 0.4; age 75 +/- 1 years (mean +/- SEM); n=53 for CSF and n=51 for plasma/red blood cell (RBC) samples]. The patients were treated with 5 or 10 mg/day donepezil and clinically followed for 2 years. The CSF and RBC AChE activities were measured by the Ellman's direct colorimetric assay. Protein levels of two variants of AChE ("read-through" AChE-R and synaptic AChE-S) were determined by an ELISA-like method.
RESULTS: The plasma donepezil concentration was dose-dependent (between 30 and 60 ng/mL in the 5-mg and 10-mg group, respectively). The CSF donepezil concentration was 10 times lower than the plasma level and showed dose- and time-dependent kinetics. The RBC AChE inhibition was moderate (19-29%). CSF AChE-S inhibition was estimated to 30-40% in the 5-mg and 45-55% in the 10-mg group. Positive correlations were observed between the CSF AChE inhibition, an increased protein level of the AChE-R variant and MMSE examination. Patients with high AChE inhibition (>or=45%) showed a stabilized MMSE test result after up to two years, while a significant decline was observed in AD patients with lower AChE inhibition (CONCLUSIONS: An increase in the protein level of the AChE-R variant corresponded to a high AChE inhibition in CSF and favored less cognitive deterioration.
ESTHER : Darreh-Shori_2006_J.Neural.Transm.(Vienna)_113_1791
PubMedSearch : Darreh-Shori_2006_J.Neural.Transm.(Vienna)_113_1791
PubMedID: 16868793

Title : Smoking during early pregnancy affects the expression pattern of both nicotinic and muscarinic acetylcholine receptors in human first trimester brainstem and cerebellum - Falk_2005_Neurosci_132_389
Author(s) : Falk L , Nordberg A , Seiger A , Kjaeldgaard A , Hellstrom-Lindahl E
Ref : Neuroscience , 132 :389 , 2005
Abstract : Prenatal nicotine exposure is associated with an increased risk of complications during pregnancy and childhood. In this study the expression of nicotinic and muscarinic acetylcholine receptors in first trimester pons, medulla oblongata and cerebellum from abortus (5-12 weeks of gestation) of smoking and nonsmoking women was compared. A significant age-related increase in binding of nicotinic receptor subtype alpha4 was found in both pons and cerebellum only in fetal tissue from non-smoking women, while a similar increase was observed in medulla oblongata from fetuses exposed to smoking. A significant age-related increase in binding of muscarinic receptor subtype m2 was observed in pons from abortus of smoking compared with non-smoking women. The gene expression pattern of both alpha4 and alpha7 nicotinic receptor subunits was changed after smoking in all three regions investigated. Smoking also changed the expression of m1 and 2 muscarinic receptor mRNA in pons, m1 mRNA in cerebellum and the m3 mRNA in medulla oblongata. The findings indicate that early prenatal nicotine exposure affects the normal developmental pattern of the cholinergic system in human fetal brain.
ESTHER : Falk_2005_Neurosci_132_389
PubMedSearch : Falk_2005_Neurosci_132_389
PubMedID: 15802191

Title : A preclinical view of cholinesterase inhibitors in neuroprotection: do they provide more than symptomatic benefits in Alzheimer's disease? - Francis_2005_Trends.Pharmacol.Sci_26_104
Author(s) : Francis PT , Nordberg A , Arnold SE
Ref : Trends in Pharmacological Sciences , 26 :104 , 2005
Abstract : The prevalence of Alzheimer's disease (AD), a neurodegenerative condition whose greatest risk factor is old age, is expected to rise dramatically during the next five decades, along with the trend for increased longevity. Early diagnosis and intervention with therapies that halt or slow disease progress are likely to represent an important component of effective treatment. Although much progress has been made in this area, there are currently no clinically approved interventions for AD that are classed as disease modifying or neuroprotective. Cholinesterase inhibitors are a drug class used for the symptomatic treatment of AD. Recent evidence from preclinical studies indicates that these agents can attenuate neuronal damage and death from cytotoxic insults, and therefore might affect AD pathogenesis. The mechanisms by which these actions are mediated might or might not be directly related to their primary mode of action.
ESTHER : Francis_2005_Trends.Pharmacol.Sci_26_104
PubMedSearch : Francis_2005_Trends.Pharmacol.Sci_26_104
PubMedID: 15681028

Title : Effect of memantine on the alpha 7 neuronal nicotinic receptors, synaptophysin- and low molecular weight MAP-2 levels in the brain of transgenic mice over-expressing human acetylcholinesterase - Unger_2005_J.Neural.Transm.(Vienna)_112_255
Author(s) : Unger C , Svedberg MM , Schutte M , Bednar I , Nordberg A
Ref : J Neural Transm (Vienna) , 112 :255 , 2005
Abstract : Transgenic mice over-expressing human acetylcholinesterase (hAChE-Tg) display memory impairments, cholinergic deficits and reduced dendritic branching. In this study, we found a reduced number of N-Methyl-D-Aspartate (NMDA) binding sites and reduced levels of low molecular weight (LMW) microtubule associated protein 2 (MAP-2), in addition to an increased number of alpha4 and alpha7 nicotinic receptor (nAChR) binding sites in the brain of hAChE-Tg mice. Treatment with memantine, 20 mg/kg/day during 14 days, significantly increased the number of [(125)I]alphabungarotoxin (alpha7 nAChR) binding sites in the frontal- and retrosplenial cortex of hAChE-Tg mice and synaptophysin- and LMW MAP-2 levels in the cortex of both hAChE-Tg and FVB/N controls. The findings reveal an alteration of the glutamatergic system in hAChE-Tg mice. Whether the effect of memantine on alpha7 nAChRs, synaptophysin- and LMW MAP-2 levels is a direct effect, or an indirect effect via the NMDA receptors, has to be further evaluated.
ESTHER : Unger_2005_J.Neural.Transm.(Vienna)_112_255
PubMedSearch : Unger_2005_J.Neural.Transm.(Vienna)_112_255
PubMedID: 15372325

Title : High selective expression of alpha7 nicotinic receptors on astrocytes in the brains of patients with sporadic Alzheimer's disease and patients carrying Swedish APP 670\/671 mutation: a possible association with neuritic plaques - Yu_2005_Exp.Neurol_192_215
Author(s) : Yu WF , Guan ZZ , Bogdanovic N , Nordberg A
Ref : Experimental Neurology , 192 :215 , 2005
Abstract : In the present study, we have investigated the expression of nicotinic acetylcholine receptors (nAChRs) on astrocytes and neurons in the hippocampus and temporal cortex of subjects carrying the Swedish amyloid precursor protein (APP) 670/671 mutation (APPswe), patients with sporadic Alzheimer's disease (AD), and age-matched control subjects. Significant increases in the total numbers of astrocytes and of astrocytes expressing the alpha7 nAChR subunit, along with significant decreases in the levels of alpha7 and alpha4 nAChR subunits on neurons, were observed in the hippocampus and temporal cortex of both APPswe and sporadic AD brains. Both of these phenomena were more pronounced in APPswe than sporadic AD cases. Furthermore, the number of [(125)I]alpha-BTX binding sites (alpha7 nAChR) in the temporal cortex of the APPswe brain was significant lower than in the younger control group, reflecting the lower neuronal level of alpha7 nAChR. The increase in the level of expression of alpha7 nAChR on astrocytes was positively correlated with the extent of neuropathological alternations, especially the number of neuritic plaques, in the AD brain. The elevated expression of alpha7 nAChR on astrocytes might participate in Abeta cascade and formation of neuritic plaques, thereby playing an important role in the pathogenesis of AD.
ESTHER : Yu_2005_Exp.Neurol_192_215
PubMedSearch : Yu_2005_Exp.Neurol_192_215
PubMedID: 15698636

Title : Preserved cognitive function after 12 months of treatment with rivastigmine in mild Alzheimer's disease in comparison with untreated AD and MCI patients - Almkvist_2004_Eur.J.Neurol_11_253
Author(s) : Almkvist O , Darreh-Shori T , Stefanova E , Spiegel R , Nordberg A
Ref : Eur Journal of Neurology , 11 :253 , 2004
Abstract : Cholinesterase inhibitors (ChEIs) have shown positive symptomatic effects on cognition, activities of daily living, and behavior in patients with Alzheimer's disease (AD). Rivastigmine is a slowly reversible ChEI that inhibits acetylcholinesterase and butyrylcholinesterase. We evaluated the effects of long-term rivastigmine treatment on cognitive function and plasma levels of ChE activity, and the relationship between ChE activity and cognition. Patients with mild AD (n = 11) treated with rivastigmine for 12 months were compared with matched groups of untreated patients with AD (n = 21) or mild cognitive impairment (MCI; n = 22) representing the natural course of the pre-clinical and very early stage of disease. For untreated AD patients, neuropsychological assessment was made at baseline and 12 months. Determination of ChE activity in plasma and assessment of global cognition, episodic memory, visuospatial ability, and attention were performed at 0 (baseline), 3, 6, and 12 months for treated AD patients and untreated MCI patients. At 12 months, cognitive function was slightly improved or maintained in mild AD patients treated with rivastigmine. In contrast, cognition was markedly worsened in untreated AD patients and unchanged or slightly worsened in untreated MCI patients. In the group of treated AD patients, there was a significant correlation between plasma ChE inhibition and cognition, particularly in relation to attention. This effect was most apparent at 3 months of treatment. In conclusion, a clear beneficial effect of rivastigmine was shown on cognitive function for patients with mild AD and plasma values of ChE inhibition were associated with attention.
ESTHER : Almkvist_2004_Eur.J.Neurol_11_253
PubMedSearch : Almkvist_2004_Eur.J.Neurol_11_253
PubMedID: 15061827

Title : Nicotine reduces A beta in the brain and cerebral vessels of APPsw mice - Hellstrom-Lindahl_2004_Eur.J.Neurosci_19_2703
Author(s) : Hellstrom-Lindahl E , Court J , Keverne J , Svedberg M , Lee M , Marutle A , Thomas A , Perry E , Bednar I , Nordberg A
Ref : European Journal of Neuroscience , 19 :2703 , 2004
Abstract : Ten days treatment with nicotine reduced insoluble amyloid A beta 1-40 and Alpha beta 1-42 peptides by 80% in the cortex of 9-month-old APPsw mice, which is more than that observed in 14.5-month-old mice following nicotine treatment for 5.5 months. A reduction in A beta associated with cerebral vessels was observed in addition to that deposited as parenchymal plaques after 5.5 months treatment. The diminution in A beta peptides observed was not accompanied by changes in brain alpha, beta or gamma secretase-like activities, NGF or BDNF protein expression measured in brain homogenates. A significant increase in sAPP was observed after nicotine treatment of SH-SY5Yneuroblastoma cells that could be blocked by the nicotinic antagonist mecamylamine. Attenuation of elevated [(125)I]-alpha bungarotoxin binding (alpha 7) in APPsw mice was observed after 5.5 months nicotine treatment. Both these observations suggest that the reduction in insoluble A beta by nicotine might be in part mediated via the alpha 7 nicotinic receptor. Further studies are required to identify potential mechanisms of the nicotine's amyloid-reducing effect.
ESTHER : Hellstrom-Lindahl_2004_Eur.J.Neurosci_19_2703
PubMedSearch : Hellstrom-Lindahl_2004_Eur.J.Neurosci_19_2703
PubMedID: 15147304

Title : Long-lasting acetylcholinesterase splice variations in anticholinesterase-treated Alzheimer's disease patients - Darreh-Shori_2004_J.Neurochem_88_1102
Author(s) : Darreh-Shori T , Hellstrom-Lindahl E , Flores-Flores C , Guan ZZ , Soreq H , Nordberg A
Ref : Journal of Neurochemistry , 88 :1102 , 2004
Abstract : Protein levels of different acetylcholinesterase (AChE) splice variants were explored by a combination of immunoblot techniques, using two different antibodies, directed against the C-terminus of the AChE-R splice variant or the core domain common to all variants. Both AChE-R and AChE-S splice variants as well as several heavier AChE complexes were detected in brain homogenates from the parietal cortex of patients with or without Alzheimer's disease (AD) as well as the cerebrospinal fluid (CSF) of AD patients, compatible with the assumption that CSF AChEs might originate from CNS neurons. Long-term changes in the composition of CSF AChE variants were further pursued in AD patients treated with rivastigmine (n = 11) or tacrine (n = 17) in comparison to untreated AD patients (n = 5). In untreated patients, AChE-R was markedly reduced as compared with the baseline level (37%), whereas the medium size AChE-S complex was increased by 32%. Intriguingly, tacrine produced a general and profound up-regulation of all detected AChE variants (up to 117%), whereas rivastigmine treatment caused a mild and selective up-regulation of AChE-R ( approximately 10%, p < 0.05). Moreover, the change in the ratio of AChE-R to AChE-S (R/S-ratio) strongly and positively correlated with sustained cognition at 12 months (p < 0.0001). Thus, evaluation of changes in the composition of CSF AChE variants may yield important information referring to the therapeutic efficacy and/or development of drug tolerance in AD patients treated with anti-cholinesterases.
ESTHER : Darreh-Shori_2004_J.Neurochem_88_1102
PubMedSearch : Darreh-Shori_2004_J.Neurochem_88_1102
PubMedID: 15009666

Title : Effect of subchronic galantamine treatment on neuronal nicotinic and muscarinic receptor subtypes in transgenic mice overexpressing human acetylcholinesterase - Svedberg_2004_Neuropharmacol_47_558
Author(s) : Svedberg MM , Bednar I , Nordberg A
Ref : Neuropharmacology , 47 :558 , 2004
Abstract : Overexpression of acetylcholinesterase (AChE) in mice causes cholinergic deficits with memory impairment. In this study, AChE overexpressing (hAChE-Tg) and control (FVB/N) mice were treated with the AChE inhibitor (AChEI) galantamine (4 mg/kg/day) for 10 days. The concentration of galantamine in plasma was 75-80 ng/ml. The inhibition of AChE was 20% in red blood cells (RBC) and 30% in brain cortical tissue. A significant increase in [(3)H]cytisine (alpha4 nicotinic receptor) binding was measured in the CA1 and CA3 area of the hippocampus of FVB/N mice following galantamine treatment. Similarly, a significant increase in [(125)I]alphabungarotoxin (alpha7 nicotinic receptor) binding was found in the frontal cortex, retrosplenial gr. cortex, motor cortex and thalamus in galantamine treated FVB/N compared to saline treated mice. No significant changes in nicotinic receptor binding sites were observed in galantamine treated hAChE-Tg mice. Significant decreases in the muscarinic receptors measured by [(3)H]AF-DX-384 (M2 muscarinic receptor) and [(3)H]pirenzepine (M1 muscarinic receptor) were observed in several brain regions of galantamine treated FVB/N and hAChE-Tg mice. This study shows regional and receptor subtype specific changes in the nicotinic receptor subtypes compared to the muscarinic receptors following galantamine treatment in FVB/N and hAChE-Tg mice.
ESTHER : Svedberg_2004_Neuropharmacol_47_558
PubMedSearch : Svedberg_2004_Neuropharmacol_47_558
PubMedID: 15380373

Title : Protein and mRNA levels of nicotinic receptors in brain of tobacco using controls and patients with Alzheimer's disease - Mousavi_2003_Neurosci_122_515
Author(s) : Mousavi M , Hellstrom-Lindahl E , Guan ZZ , Shan KR , Ravid R , Nordberg A
Ref : Neuroscience , 122 :515 , 2003
Abstract : The neuronal nicotinic receptors (nAChRs) are involved in several processes in brain including nicotine dependence and cognitive disorders. While the number of nAChRs in the brain of tobacco smokers is up-regulated, the receptors are reduced in the brain of patients with Alzheimer's disease (AD). The aim of this study was to investigate nAChR mRNA and protein levels in brain of smoking and non-smoking controls and AD patients. Western blotting and RT-PCR techniques were used to quantify different nAChR subunits in autopsy brain. The alpha4 and alpha7 but not the alpha3 nAChR protein levels were significantly increased in the temporal cortex of smoking (SC) compared with non-smoking controls (NSC). The alpha4-protein level was significantly higher in the temporal cortex of smoking AD (SAD) patients compared with non-smoking AD (NSAD). No changes in the alpha3, alpha4 or alpha7 subunits protein level were found in the hippocampus in any of the smoking groups. For both SADs and NSADs the protein levels for the alpha3 and alpha4 in temporal cortex and hippocampus and alpha7 in the hippocampus were significantly lower compared with non-smoking controls. No significant differences in alpha4 and alpha7 mRNA levels were detected in the hippocampus or temporal cortex of smokers compared with non-smokers. In conclusion this study showed an increased level of alpha4 and alpha7 nAChRs subunits in the temporal cortex of SC compared with NSC. This up-regulation was also seen in SAD although the protein levels of nAChR subunits were still lower in smoking AD brain compared with the NSC. The up-regulation of nAChRs in smoking groups and the loss of these receptors in AD patients were not correlated to any changes at the mRNA level suggesting that these changes may reflect post-transcriptional events.
ESTHER : Mousavi_2003_Neurosci_122_515
PubMedSearch : Mousavi_2003_Neurosci_122_515
PubMedID: 14614915

Title : Toward an early diagnosis and treatment of Alzheimer's disease - Nordberg_2003_Int.Psychogeriatr_15_223
Author(s) : Nordberg A
Ref : Int Psychogeriatr , 15 :223 , 2003
Abstract : Alzheimer's disease (AD) is the most common neurodegenerative disease. There has been a rapid increase in the knowledge of epidemiology, genetics, risk factors, and underlying neuropathological mechanisms, but still there is no cure for AD. Recent promising studies with functional imaging using positron emission tomography (PET) and magnetic resonance imaging reveal that disease processes can be detected when very early subjective symptoms of AD are manifest. Recently the PET ligand PIB was reported to bind in vivo to beta-amyloid in the brains of AD patients. Also cerebrospinal fluid markers including tau, phosphotau, and A beta 1-42 are probably important early biological markers that will provide an early diagnosis of AD. An obvious impairment in central cholinergic transmitter function and its close relation to cognitive function led to the development of the acetylcholinesterase inhibitors that now are used as symptomatic therapy. A drug interfering with the glutaminergic brain transmitter system, the NMDA antagonist memantine, has recently been approved for the treatment of patients with severe AD. In order to stop or reverse disease progression, different AD treatment strategies are of great interest. Epidemiological studies support the hypothesis that long-term treatment with estrogen, antioxidants, anti-inflammatory drugs, and cholesterol-lowering agents could protect against the development of AD. Treatment with these drugs in manifest AD has been less promising. The use of nerve growth factors was limited by severe side effects. Much evidence supports the key role of beta-amyloid in the pathogenesis of AD. Compounds such as amyloid beta-sheet breakers, cholesterol-lowering drugs, estrogen, nicotine, zinc and copper chelators, inhibitors of beta- and gamma-secretases, and immunization to reduce the amyloid burden in transgenic mice overexpressing beta-amyloid all have their advocates. The latter exciting strategy turned out to cause meningoencephalitis in 6% of AD patients so treated. One patient from the trial has died showing less beta-amyloid burden in brain than expected and patients with serum beta-amyloid plaque reactive antibodies had less cognitive decline after 1 year than AD patients without antibodies. There is a great optimism for early diagnosis and effective treatment of AD in the future.
ESTHER : Nordberg_2003_Int.Psychogeriatr_15_223
PubMedSearch : Nordberg_2003_Int.Psychogeriatr_15_223
PubMedID: 14756159

Title : Higher expression of alpha7 nicotinic acetylcholine receptors in human fetal compared to adult brain - Falk_2003_Brain.Res.Dev.Brain.Res_142_151
Author(s) : Falk L , Nordberg A , Seiger A , Kjaeldgaard A , Hellstrom-Lindahl E
Ref : Brain Research Developmental Brain Research , 142 :151 , 2003
Abstract : Neuronal nicotinic acetylcholine receptors are thought to be involved in regulation of several processes during neurogenesis of the brain. In this study the expression of the alpha7 nicotinic acetylcholine receptor subtype was investigated in human fetal (9-11 weeks of gestation), middle-aged (28-51 years) and aged (68-94 years) medulla oblongata, pons, frontal cortex, and cerebellum. The specific binding of the alpha7 receptor antagonist [(125)I]alpha-bungarotoxin was significantly higher in fetal than in both middle-aged and aged medulla oblongata and aged pons. No significant decrease in [(125)I]alpha-bungarotoxin binding sites was observed from fetal to adult cortex and cerebellum. The alpha7 mRNA expression was significantly higher in all fetal brain regions investigated, except for aged cortex, than in corresponding middle-aged and aged tissue. The high expression of alpha7 nicotinic acetylcholine receptors in fetal compared to adult brain supports the view that these receptors play an important role during brain development.
ESTHER : Falk_2003_Brain.Res.Dev.Brain.Res_142_151
PubMedSearch : Falk_2003_Brain.Res.Dev.Brain.Res_142_151
PubMedID: 12711366

Title : Neuronal nicotinic and muscarinic receptor subtypes at different ages of transgenic mice overexpressing human acetylcholinesterase - Svedberg_2003_Neurosci.Lett_340_148
Author(s) : Svedberg MM , Svensson AL , Bednar I , Nordberg A
Ref : Neuroscience Letters , 340 :148 , 2003
Abstract : Subtypes of nicotinic (alpha4 and alpha7) as well as muscarinic (M1 and M2) receptor binding sites were quantified in the brain of transgenic mice overexpressing human acetylcholinesterase (AChE) at different ages using selective radioligands. A significant increase in [(3)H]cytisine (alpha4) binding was found in the cortex and striatum of AChE transgenic (hAChE-Tg) mice from 3 days to 12 months of age in comparison to non-transgenic mice. In addition a significant increase in [(3)H]AF-DX-384 (M2) binding was found in the striatum of hAChE-Tg mice at 3 months of age compared to controls. No major alteration was observed in the [(125)I]alpha-bungarotoxin (alpha7) or the [(3)H]pirenzepine (M1) binding sites. The persistent increase in alpha4 and M2 receptor binding sites in hAChE-Tg mice suggests that these receptor subtypes may play an important role in compensatory mechanisms facilitating the impaired cholinergic neurotransmission in hAChE-Tg.
ESTHER : Svedberg_2003_Neurosci.Lett_340_148
PubMedSearch : Svedberg_2003_Neurosci.Lett_340_148
PubMedID: 12668258

Title : Cerebral glucose metabolism, cerebrospinal fluid-beta-amyloid(1-42) (CSF-Abeta42), tau and apolipoprotein E genotype in long-term rivastigmine and tacrine treated Alzheimer disease (AD) patients - Stefanova_2003_Neurosci.Lett_338_159
Author(s) : Stefanova E , Blennow K , Almkvist O , Hellstrom-Lindahl E , Nordberg A
Ref : Neuroscience Letters , 338 :159 , 2003
Abstract : We evaluated cerebral glucose metabolism (CMRglc) and cerebrospinal fluid (CSF) levels of tau and beta-amyloid(1-42) (Abeta42), in relation to apolipoprotein E (ApoE) genotype, in patients with mild Alzheimer disease (AD) treated with rivastigmine (n=11) and tacrine (n=16) for 1 year; and two untreated AD groups. The rivastigmine-treated AD patients showed a significant increase in CMRglc as compared to both tacrine-treated and untreated AD subjects. The rivastigmine-treated AD group showed no change in CSF-tau levels after 1 year, while in contrast a significant increase as seen in tacrine-treated and untreated AD patients. The CSF-tau changes were mainly seen in ApoE epsilon4 carriers. There was no significant change in Abeta42 after 1-year treatment with either rivastigmine or tacrine. This study shows that the two long-term cholinesterase inhibitor treatments exert different effects on biological markers for AD.
ESTHER : Stefanova_2003_Neurosci.Lett_338_159
PubMedSearch : Stefanova_2003_Neurosci.Lett_338_159
PubMedID: 12566177

Title : Chronic nicotine treatment reduces beta-amyloidosis in the brain of a mouse model of Alzheimer's disease (APPsw) - Nordberg_2002_J.Neurochem_81_655
Author(s) : Nordberg A , Hellstrom-Lindahl E , Lee M , Johnson M , Mousavi M , Hall R , Perry E , Bednar I , Court J
Ref : Journal of Neurochemistry , 81 :655 , 2002
Abstract : Alzheimer's disease neuropathology is characterised by beta-amyloid plaques and neurofibrillary tangles. Inhibition of beta-amyloid accumulation may be essential for effective therapy in Alzheimer's disease. In this study we have treated transgenic mice carrying the Swedish mutation of human amyloid precursor protein [Tg(Hu.APP695.K670N-M671L)2576], which develop brain beta-amyloid deposits, with nicotine in drinking fluid (200 microg/mL) from 9-14.5 months of age (5.5 months). A significant reduction in amyloid beta peptide 1-42 positive plaques by more than 80% (p < 0.03) was observed in the brains of nicotine treated compared to sucrose treated transgenic mice. In addition, there was a selective reduction in extractable amyloid beta peptides in nicotine treated mice; cortical insoluble 1-40 and 1-42 peptide levels were lower by 48 and 60%, respectively (p < 0.005), whilst there was no significant change in soluble 1-40 or 1-42 levels. The expression of glial fibrillary acidic protein was not affected by nicotine treatment. These results indicate that nicotine may effectively reduce amyloid beta peptide aggregation in brain and that nicotinic drug treatment may be a novel protective therapy in Alzheimer's disease.
ESTHER : Nordberg_2002_J.Neurochem_81_655
PubMedSearch : Nordberg_2002_J.Neurochem_81_655
PubMedID: 12065674

Title : Sustained cholinesterase inhibition in AD patients receiving rivastigmine for 12 months - Darreh-Shori_2002_Neurology_59_563
Author(s) : Darreh-Shori T , Almkvist O , Guan ZZ , Garlind A , Strandberg B , Svensson AL , Soreq H , Hellstrom-Lindahl E , Nordberg A
Ref : Neurology , 59 :563 , 2002
Abstract : OBJECTIVE: To study the long-term dual inhibitory effects of rivastigmine on acetylcholinesterase (AChE) and butyrylcholinesterase (BCHE) in patients with AD.
METHODS: Eleven patients with mild AD received rivastigmine for 12 months. Cholinesterase (ChE) activities in the CSF and plasma were assessed colorimetrically. Immunoblot analysis was used to evaluate AChE isoforms. Neuropsychiatric tests were performed throughout the study.
RESULTS: At 12 months, the mean dose of rivastigmine was 8.6 mg/d and specific activities of ChE in the CSF were lower than baseline values (by 36% for AChE and 45% for BCHE), correlating with parallel reductions in the plasma (27% for AChE and 33% for BCHE). The reduction of specific activities in the CSF, but not in the plasma, appeared to be dependent on the dose and duration of treatment. Scores of some of the neuropsychological tests associated with memory and attention were correlated with both plasma and CSF AChE and BCHE inhibition for up to 6 months. Immunoblot analysis revealed up-regulation of the "read-through" AChE isoform (AChE-R), whereas levels of the synaptic isoform were unchanged.
CONCLUSIONS: Rivastigmine causes persistent inhibition of AChE and BCHE in CSF as well as plasma. The persistent CSF inhibition contrasts with earlier findings after long-term treatment by the reversible ChE inhibitor tacrine, which demonstrated increased AChE activity in the CSF but not in the blood. Rivastigmine's effects on the preferential up-regulation of the AChE-R isoform may have a favorable effect on disease stabilization.
ESTHER : Darreh-Shori_2002_Neurology_59_563
PubMedSearch : Darreh-Shori_2002_Neurology_59_563
PubMedID: 12196650

Title : Upregulation of neuronal nicotinic receptor subunits alpha4, beta2, and alpha7 in transgenic mice overexpressing human acetylcholinesterase - Svedberg_2002_J.Mol.Neurosci_18_211
Author(s) : Svedberg MM , Svensson AL , Johnson M , Lee M , Cohen O , Court J , Soreq H , Perry E , Nordberg A
Ref : Journal of Molecular Neuroscience , 18 :211 , 2002
Abstract : Neuronal nicotinic receptor binding sites as well as mRNA levels encoding for subunits alpha4, beta2, and alpha7 were analysed in 3-mo-old transgenic mice generated with a neuronal overexpression of human acetylcholinesterase and in age-matched controls. The acetylcholinesterase transgenic mice display progressive cognitive impairment in spatial learning and memory. We here report a significantly increased [3H]epibatidine and [125I]alphabungarotoxin binding in the cortex and the caudate putamen of these mice. Quantitativein situ hybridization showed significant upregulation of mRNA corresponding to the nicotinic receptor subunits alpha4, beta2, and alpha7 in various brain regions in the transgenic mice compared to nontransgenic controls. Our results suggest that disruption of balanced cholinergic transmission by constitutive overexpression of acetylcholinesterase is accompanied by variable upregulation of several nicotinic receptor subtypes, in particular these associated with cholinergic terminals participating in compensatory response.
ESTHER : Svedberg_2002_J.Mol.Neurosci_18_211
PubMedSearch : Svedberg_2002_J.Mol.Neurosci_18_211
PubMedID: 12059039

Title : The alpha7 nicotinic receptors in human fetal brain and spinal cord - Falk_2002_J.Neurochem_80_457
Author(s) : Falk L , Nordberg A , Seiger A , Kjaeldgaard A , Hellstrom-Lindahl E
Ref : Journal of Neurochemistry , 80 :457 , 2002
Abstract : The alpha7 nicotinic acetylcholine receptor subtype is believed to be involved in the regulation of neuronal growth, differentiation and synapse formation during the development of the human brain. In this study the expression of the alpha7 nicotinic acetylcholine receptor was investigated in human fetal brain and spinal cord of 5-11 weeks gestational age. Both the specific binding of [125I]alpha-bungarotoxin to prenatal brain membranes and the expression of alpha7 mRNA were significantly higher in the pons, medulla oblongata, mesencephalon and spinal cord of 9-11 weeks gestational age compared with cerebellum, cortex and subcortical forebrain. A significant positive correlation between gestational age and the expression of alpha7 mRNA was observed in all brain regions except cortex. A positive correlation was also observed between the gestational age and the [125I]alpha-bungarotoxin binding in the pons, medulla oblongata, mesencephalon, and cerebellum. Consequently, a significant relationship between the alpha7 mRNA levels and the binding sites for [125I]alpha-bungarotoxin was found in the fetal brain. The increasing levels of the alpha7 nicotinic acetylcholine receptor during the first trimester support the important role of nAChRs for the development of the central nervous system.
ESTHER : Falk_2002_J.Neurochem_80_457
PubMedSearch : Falk_2002_J.Neurochem_80_457
PubMedID: 11905992

Title : Chronic treatments with tacrine and (-)-nicotine induce different changes of nicotinic and muscarinic acetylcholine receptors in the brain of aged rat - Zhang_2002_J.Neural.Transm_109_377
Author(s) : Zhang X , Tian JY , Svensson AL , Gong ZH , Meyerson B , Nordberg A
Ref : J Neural Transm , 109 :377 , 2002
Abstract : The present study evaluated effects of chronic treatment with tacrine and (-)-nicotine for 21 days on nicotinic and muscarinic acetylcholine receptors in the brains of old rats (24-25 months) by receptor autoradiography. The nicotinic receptor (nAChR) binding sites were measured by (-)-[3H]nicotine and [3H]epibatidine, and the muscarinic receptor (mAChR) binding sites by [3H]pirenzepine and [3H]AFDX 384. No change in (-)-[3H]nicotine binding was observed in all of the brain regions analysed following chroinic treatment with tacrine (10 mg/kg). Similarly, the [3H]epibatidine binding was not changed in most of the brain regions analysed except for a few brain regions where a decrease was observed in tacrine treated animals compared to control animals. Chronic treatment with (-)-nicotine (0.45 mg base/kg) significantly increased both (-)-[3H]nicotine and [3H]epibatidine bindings in every brain regions analysed except for the hippocampus when measured by (-)-[3H]nicotine. A significant decrease in [3H]AFDX 384 binding, but not in [3H]pirenzepine binding was observed in all of the brain regions analysed following the treatment with tacrine. These data suggest that chronic treatments with tacrine and (-)-nicotine differentially interfere and regulate the subtypes of nAChRs and mAChRs in the brain of aged rat. These data differ from what have been earlier observed in the brain of young adult rat following tacrine treatment, revealing some dynamic changes in receptor properties in the brain during aging.
ESTHER : Zhang_2002_J.Neural.Transm_109_377
PubMedSearch : Zhang_2002_J.Neural.Transm_109_377
PubMedID: 11956958

Title : Selective changes in the levels of nicotinic acetylcholine receptor protein and of corresponding mRNA species in the brains of patients with Parkinson's disease - Guan_2002_Brain.Res_956_358
Author(s) : Guan ZZ , Nordberg A , Mousavi M , Rinne JO , Hellstrom-Lindahl E
Ref : Brain Research , 956 :358 , 2002
Abstract : Reductions in the number of neuronal nicotinic acetylcholine receptors (nAChRs) have been shown to occur in connection with Parkinson's disease (PD), but it is still unclear which subtype of this receptor is affected. In the present study we examined various nAChR subtypes employing ligand binding, as well as levels of subunit protein and mRNA in the brains of PD patients and age-matched controls. Binding of [3H]epibatidine and levels of alpha3 mRNA in the caudate nucleus and temporal cortex, but not in the hippocampus were significantly decreased in the PD brain. The level of the alpha3 protein subunit was significantly reduced in all these brain regions but there was no change in the level of alpha4. The level of the beta2 protein subunit in the temporal cortex and hippocampus and the beta2 mRNA in the temporal cortex was lowered. Both the levels of the alpha7 subunit protein and [125I]alpha-bungarotoxin binding were significantly increased in the temporal cortex of PD patients whereas the alpha7 mRNA level was unchanged. These findings reveal selective losses of the alpha3- and beta2-containing nAChRs and an increase in the alpha7 nAChRs that might be related to the pathogenesis of PD.
ESTHER : Guan_2002_Brain.Res_956_358
PubMedSearch : Guan_2002_Brain.Res_956_358
PubMedID: 12445706

Title : Selective nicotinic receptor consequences in APP(SWE) transgenic mice - Bednar_2002_Mol.Cell.Neurosci_20_354
Author(s) : Bednar I , Paterson D , Marutle A , Pham TM , Svedberg M , Hellstrom-Lindahl E , Mousavi M , Court J , Morris C , Perry E , Mohammed A , Zhang X , Nordberg A
Ref : Molecular & Cellular Neurosciences , 20 :354 , 2002
Abstract : The nicotinic (nAChRs) and muscarinic (mAChRs) acetylcholine receptors and acetylcholinesterase (AChE) activity were studied in the brains of APP(SWE) transgenic mice (Tg+) and age-matched nontransgenic controls (Tg-) that were between 4 and 19 months of age. A significant increase in the binding of 125I-labeled alpha-bungarotoxin (alpha7 nAChRs) was observed in most brain regions analyzed in 4-month-old Tg+ mice, preceding learning and memory impairments and amyloid-beta (Abeta) pathology. The enhanced alpha7 receptor binding was still detectable at 17-19 months of age. Increase in [3H]cytisine binding (alpha4beta2 nAChRs) was measured at 17-19 months of age in Tg+ mice, at the same age when the animals showed heavy Abeta pathology. No significant changes in [3H]pirenzepine (M1 mAChRs) or [3H]AFDX 384 (M2 mAChRs) binding sites were found at any age studied. The upregulation of the nAChRs probably reflects compensatory mechanisms in response to Abeta burden in the brains of Tg+ mice.
ESTHER : Bednar_2002_Mol.Cell.Neurosci_20_354
PubMedSearch : Bednar_2002_Mol.Cell.Neurosci_20_354
PubMedID: 12093166

Title : Expression of nicotinic acetylcholine receptors in human and rat adrenal medulla - Mousavi_2001_Life.Sci_70_577
Author(s) : Mousavi M , Hellstrom-Lindahl E , Guan ZZ , Bednar I , Nordberg A
Ref : Life Sciences , 70 :577 , 2001
Abstract : Neuronal nicotinic receptors (nAChRs) are expressed in the brain but also in the peripheral tissues including the adrenal medulla. However, it is unclear which nAChRs are present in the human adrenal medulla. In the study, receptor binding assay, Western blot and RT-PCR have been performed to investigate the expression of nAChRs in adrenal medulla from human, rat and mouse. The results showed that in human adult adrenal medulla, mRNAs for nAChR alpha3, alpha4, alpha5, alpha7, beta2, beta3, and beta4 subunits but not beta2 in the fetal human adrenal medulla were expressed. Saturation binding of [3H]epibatidine showed two binding sites in human aged adrenal medulla. The specific binding of [3H]epibatidine (0.1 nM) was significantly higher in human fetal compared to human aged adrenal medulla. mRNAs for the alpha3, alpha4, alpha5, alpha7, beta2, and beta4 subunits but not the beta3 were detectable in adult rat and mouse adrenal medulla. No differences in gene-expression of the nAChRs were observed between new born, adult and aged rat adrenal medulla. Saturation binding of [3H]epibatidine showed only one binding site in rat adrenal medulla. Lower protein levels for the nAChR subunits were observed in the rat adrenal medulla compared to rat brain. There was lower protein levels of the nAChRs in aged rat adrenal medulla compared to the young rats. Sub-chronic treatment of nicotine to rats did not influence level of the nAChRs in the adrenal medulla. In conclusion, the expression of nAChRs in adrenal medulla is age- related and species dependent.
ESTHER : Mousavi_2001_Life.Sci_70_577
PubMedSearch : Mousavi_2001_Life.Sci_70_577
PubMedID: 11811902

Title : Responder characteristics to a single oral dose of cholinesterase inhibitor: a double-blind placebo-controlled study with tacrine in Alzheimer patients - Almkvist_2001_Dement.Geriatr.Cogn.Disord_12_22
Author(s) : Almkvist O , Jelic V , Amberla K , Hellstrom-Lindahl E , Meurling L , Nordberg A
Ref : Dementia & Geriatric Cognitive Disorders , 12 :22 , 2001
Abstract : A proportion of Alzheimer's disease (AD) patients treated for several months with cholinesterase (ChE) inhibitors have shown some favorable response on cognition, but the characteristics of the responders are still unclear. This study attempts to identify the characteristics of individuals with a positive behavioral response after a double-blind randomized administration of a single oral dose of tacrine (40 mg) and placebo to AD patients. Furthermore, the relationship between single-dose and long-term responders are examined. Twenty-four mildly to very mildly demented AD patients participated in the study. They all fulfilled the diagnosis of probable AD according to NINCDS-ADRDA criteria. Active treatment (tacrine 40 mg) and placebo was administered in random order on 2 consecutive days, and the effects were evaluated within 2 h using neuropsychological tests (assessing visuospatial ability, episodic memory and attention), registration of EEG activity and measurement of red blood cells (RBC) acetylcholinesterase (AChE), ChE activity and concentrations of tacrine and its metabolites in plasma. Results demonstrated significant improvement, tacrine compared to placebo, in measures of attention, but not in episodic memory or visuospatial ability. A single-dose response was therefore defined in terms of improvement in attention. The tacrine plasma concentration (pcTHA) showed a positively skewed distribution (mean +/- SD: 10.5 +/- 11.8, range: 1.0-51.8 ng/ml). There were no significant differences between single-dose responders compared to nonresponders in pcTHA, metabolites of tacrine, inhibition of AChE in RBC, tau levels in CSF, AChE activity in CSF or plasma and demographic variables. However, single-dose responders showed a higher right frontal alpha/theta ratio on EEG and had lower glucose metabolism in the parietal-temporal association cortex at baseline. In addition, the frequency of apolipoprotein E (APOE) epsilon 4 alleles was higher in responders. Interestingly, the single-dose response was related to the long-term response, although not significantly, which probably was due to lack of power. To conclude, the present study identified single-dose responders in terms of improved attentional performance associated with a relatively higher alpha/theta activity in the right frontal regions of the brain measured on EEG and predominance of APOE epsilon 4 allele.
ESTHER : Almkvist_2001_Dement.Geriatr.Cogn.Disord_12_22
PubMedSearch : Almkvist_2001_Dement.Geriatr.Cogn.Disord_12_22
PubMedID: 11125238

Title : Nicotine-induced alterations in the expression of nicotinic receptors in primary cultures from human prenatal brain - Hellstrom-Lindahl_2001_Neurosci_105_527
Author(s) : Hellstrom-Lindahl E , Seiger A , Kjaeldgaard A , Nordberg A
Ref : Neuroscience , 105 :527 , 2001
Abstract : The nicotinic receptor proteins and gene transcripts for the different nicotinic receptor subunits exist in human prenatal brain already at 4-5 weeks of gestation. The early presence of nicotinic receptors suggests an important role for these receptors in modulating dendritic outgrowth, establishment of neuronal connections and synaptogenesis during development. When measurements of nicotinic receptors using [(3)H]epibatidine (labelling both the alpha3 and alpha4 subtype) and [(3)H]cytisine (labelling the alpha4 subtype) were performed in intact cells from the cortex, subcortical forebrain and mesencephalon (7.5-11 weeks of gestation), the highest specific binding for both ligands was detected in cells from mesencephalon, followed by subcortical forebrain and cortex. The effects of nicotine exposure were studied in primary cultures of prenatal brain (7.5-11 weeks of gestation). Treatment with nicotine (1-100 microM) for 3 days significantly increased the specific binding of [(3)H]epibatidine and [(3)H]cytisine in cortical cells but not in cells from subcortical forebrain and mesencephalon brain regions, indicating region-specific differences in the sensitivity to nicotine exposure. Relative quantification of mRNA showed that the expression of the nicotinic receptor subunits alpha3 and alpha7, but not alpha4, was increased in cortical cells after nicotine treatment. These findings support the assumption of a potential risk of disturbance in the functional role of nicotinic receptors during brain development as a consequence of maternal smoking during pregnancy.
ESTHER : Hellstrom-Lindahl_2001_Neurosci_105_527
PubMedSearch : Hellstrom-Lindahl_2001_Neurosci_105_527
PubMedID: 11516820

Title : Increased levels of tau protein in SH-SY5Y cells after treatment with cholinesterase inhibitors and nicotinic agonists - Hellstrom-Lindahl_2000_J.Neurochem_74_777
Author(s) : Hellstrom-Lindahl E , Moore H , Nordberg A
Ref : Journal of Neurochemistry , 74 :777 , 2000
Abstract : Several cholinesterase inhibitors used in the treatment of Alzheimer's disease (AD) have been shown to interact with an allosteric site on the nicotinic acetylcholine receptor (nAChR). A possible linkage between the phosphorylation state of tau, the major component of paired helical filaments found in AD brain, and stimulation of nAChRs by cholinesterase inhibitors and nicotinic agonists was investigated. Western blot analysis showed that treatment of SH-SY5Y cells for 72 h with the cholinesterase inhibitors tacrine (10(-5) M), donepezil (10(-5) M), and galanthamine (10(-5) M), nicotine (10(-5) M), and epibatidine (10(-7) M) increased tau levels as detected with Tau-1, AT 8, and AT 270 monoclonal antibodies and binding of [3H]epibatidine. The increase in tau immunoreactivity induced by nicotine, epibatidine, and tacrine, but not the up-regulation of nAChRs, was prevented by the antagonists d-tubocurarine and mecamylamine. Both antagonists were synergistic with the nicotinic agonists in causing up-regulation, but only d-tubocurarine showed a synergistic effect with tacrine. The increased tau immunoreactivity induced by tacrine was not prevented by atropine, indicating that in terms of cholinergic receptors, tacrine modulates tau levels mainly through interactions with nAChRs and not with muscarinic receptors. Additional work is needed to determine the exact mechanism by which cholinesterase inhibitors and nicotinic agonists modulate phosphorylation and levels of tau protein.
ESTHER : Hellstrom-Lindahl_2000_J.Neurochem_74_777
PubMedSearch : Hellstrom-Lindahl_2000_J.Neurochem_74_777
PubMedID: 10646530

Title : Neuroprotection in Alzheimer's disease - new strategies for treatment - Nordberg_2000_Neurotox.Res_2_157
Author(s) : Nordberg A
Ref : Neurotox Res , 2 :157 , 2000
Abstract : Alzheimer's disease is the most common dementia disorder characterized by multiple pathological changes in the brain leading to a progressive memory loss and other cognitive symptoms producing occupational and social disabilities. Although a great deal of progress has been made in recent years in further understanding the genetic aberrations and patho-physiological processes of Alzheimer's disease there is still no cure of the disease. The transmitter replacement therapy is so far the most explored therapy. Three cholinesterase inhibitors have so far been approved and presently in clinical use in many countries. Although the cholinesterase inhibitors generally appear to produce symptomatic effects with palliative effect on existing cognitive disturbances recent data suggest that they also may have effect on progression of the disease including possible neuroprotective effects. Possible interactions between Abeta and cholinergic neurotransmission may exist. Treatment of cells with Abeta causes decreased cholinergic activity. Pretreatment of PC12 cells with cholinesterase inhibitors such as tacrine and donepezil in clinical relevant concentrations can attenuate Abeta (25-35) toxicity through mechanisms which may be mediated via nicotinic receptors. Estrogen has been shown to protect against Abeta toxicity in different cell lines and also to reduce the formation of Abeta. Its mechanism for the neuroprotective effect is however not fully clarified. A potentiation of the clinical effect of cholinesterase inhibitors in Alzheimer patients has been given together with estrogen. Experimental data suggest that the neuroprotective effect of estrogen as studied in PC12 cells was mediated at least partly via the alpha(7) nicotinic receptor. Treatment with Abeta in nanomolar concentrations for 7 days in PC12 cells significantly decreased the number of nicotinic receptor binding sites and mRNA levels. The effects by Abeta on nicotinic receptors are prevented by nicotine pretreatment. The finding suggests a possible link between Abeta and nicotinic receptor deficits in Alzheimer patients in the early course of the disease.
ESTHER : Nordberg_2000_Neurotox.Res_2_157
PubMedSearch : Nordberg_2000_Neurotox.Res_2_157
PubMedID: 16787838

Title : Noninvasive Exploration of Nicotinic Acetylcholine Receptors In Vivo -
Author(s) : Nordberg A
Ref : Handbook of Experimental Pharmacology , 144 :539 , 2000
PubMedID:

Title : Neuronal nicotinic receptors in the human brain - Paterson_2000_Prog.Neurobiol_61_75
Author(s) : Paterson D , Nordberg A
Ref : Prog Neurobiol , 61 :75 , 2000
Abstract : Neuronal nicotinic acetylcholine receptors (nAChRs) are a family of ligand gated ion channels which are widely distributed in the human brain. Multiple subtypes of these receptors exist, each with individual pharmacological and functional profiles. They mediate the effects of nicotine, a widely used drug of abuse, are involved in a number of physiological and behavioural processes and are additionally implicated in a number of pathological conditions such as Alzheimer's disease, Parkinson's disease and schizophrenia. The nAChRs have a pentameric structure composed of five membrane spanning subunits, of which nine different types have thus far been identified and cloned. The multiple subunits identified provide the basis for the heterogeneity of structure and function observed in the nAChR subtypes and are responsible for the individual characteristics of each. A substantial amount of information on human nAChR structure and function has come from studies on neuroblastoma cell lines which naturally express nAChRs and from recombinant nAChRs expressed in Xenopus oocytes. In vitro brain nAChR distribution can be mapped with a number of appropriate agonist and antagonist radioligands and subunit distribution may be mapped by in situ hybridization using subunit specific mRNA probes. Receptor distribution in the living human brain can be studied with noninvasive imaging techniques such as PET and SPECT, with a significant reduction in nAChRs in the brains of Alzheimer's patients having been identified with [11C] nicotine in PET studies. Despite the significant body of knowledge now accumulated about nAChRs, much remains to be elucidated. This review will attempt to describe the current knowledge on the nAChR subtypes in the human brain, their functional roles and neuropathological involvement.
ESTHER : Paterson_2000_Prog.Neurobiol_61_75
PubMedSearch : Paterson_2000_Prog.Neurobiol_61_75
PubMedID: 10759066

Title : Development of ligands for in vivo imaging of cerebral nicotinic receptors - Sihver_2000_Behav.Brain.Res_113_143
Author(s) : Sihver W , Nordberg A , Langstrom B , Mukhin AG , Koren AO , Kimes AS , London ED
Ref : Behavioural Brain Research , 113 :143 , 2000
Abstract : Nicotinic acetylcholine receptors (nAChRs) mediate a variety of brain functions. Findings from postmortem studies and clinical investigations have implicated them in the pathophysiology and treatment of Alzheimer's and Parkinson's diseases and other CNS disorders (e.g. Tourette's syndrome, epilepsy, nicotine dependence). Therefore, it ultimately might be useful to image nAChRs noninvasively for diagnosis, for studies on how changes in nAChRs might contribute to cerebral disorders, for development of therapies targeted at nAChRs, and to monitor the effects of such treatments. To date, only (S)-(-)-nicotine, radiolabeled with 11C, has been used for external imaging of nAChRs in human subjects. Since this radiotracer presents drawbacks, new ligands, with more favorable properties, have been synthesized and tested. Three general classes of compounds, namely, nicotine and its analogs, epibatidine and related compounds, and 3-pyridyl ether compounds, including A-85380, have been evaluated. Analogs of A-85380 appear to be the most promising candidates because of their low toxicity and high selectivity for the alpha4beta2 subtype of nAChRs.
ESTHER : Sihver_2000_Behav.Brain.Res_113_143
PubMedSearch : Sihver_2000_Behav.Brain.Res_113_143
PubMedID: 10942041

Title : PET studies and cholinergic therapy in Alzheimer's disease - Nordberg_1999_Rev.Neurol_155_S53
Author(s) : Nordberg A
Ref : Rev Neurol , 155 :S53 , 1999
Abstract : Alzheimer's disease (AD) is one of the most devastating brain disorders of elderly humans. The last decade has witnessed a steadily increasing effort directed at discovery of the etiology of the disease and development of pharmacological treatment stategies. Symptomatic treatment mainly focussing on cholinergic therapy has been clinical evaluated by randomized, double-blind, placebo controlled, parallel group studies measuring performance based tests of cognitive function, activity of daily living and behavior. Significant progress has been made in recent years to develop and apply functional brain imaging techniques allowing early diagnosis of dementia and evaluation of treatment efficacy. Positron emission tomography (PET) is a suitable method for functional studies of pathological changes in brain which as a clinical instrument not solely reveal dysfunctional changes early in the course of the disease but also may provide a deep insight into the functional mechanisms of new potential drug treatment strategies. The advantage with PET is the capacity not only to measure changes in glucose metabolism, cerebral blood flow but also to obtain further insight into neuronal communicative processes (transmitter/receptor interactions) in brain and pharmacokinetic events and drug mechanisms. PET studies have so far revealed disturbances in some neuroreceptor systems in brain of AD patients. A significant correlation can be observed between the impairment of nicotinic receptors in the temporal cortex and the cognitive impairment of AD patients. Cholinergic drugs including cholinesterase inhibitors such as physostigmine, tacrine, velnacrine as well as the acetylcholine releaser linopiridine have been reported to increase the cerebral blood flow in AD patients both after acute and fairly short period of treatment. Increase in cerebral glucose metabolism has also been measured following fairly long periods of treatment with cholinesterase inhibitors (months). The cholinergic nicotinic and muscarinic receptors do also respond to treatment with cholinesterase inhibitors in AD patients. An improvement of the nicotinic receptors has been found in cortical regions following treatment with cholinesterase inhibitors and nerve growth factors (NGF) to AD patients. Functional PET activation studies performed simultaneously with memory tasks will provide further valuable insight into the mechanisms of action of new drug, how they interact and can improve the efficacy of memory processes in AD brains.
ESTHER : Nordberg_1999_Rev.Neurol_155_S53
PubMedSearch : Nordberg_1999_Rev.Neurol_155_S53
PubMedID: 10637939

Title : Autoradiographic comparison of [3H](-)nicotine, [3H]cytisine and [3H]epibatidine binding in relation to vesicular acetylcholine transport sites in the temporal cortex in Alzheimer's disease - Sihver_1999_Neurosci_94_685
Author(s) : Sihver W , Gillberg PG , Svensson AL , Nordberg A
Ref : Neuroscience , 94 :685 , 1999
Abstract : The laminar binding distribution of three nicotinic receptor agonists, [3H](-)nicotine, [3H]cytisine, and [3H]epibatidine, and their relation to the [3H]vesamicol binding, which is known to represent the vesicular acetylcholine transport sites, was performed employing in vitro autoradiography on the medial temporal cortex (Brodmann area 21). Autopsied brain tissue from nine Alzheimer patients and seven age-matched controls were used. The binding pattern of the three nicotinic ligands in the normal cortex was in general similar, showing binding maxima in the cortical layers I, III and V. The binding of [3H](-)nicotine, [3H]cytisine, and [3H]epibatidine was lower in the older controls and more uniform throughout the layers as compared with younger controls. There was a significant age-related decrease in the binding of the three nicotinic ligands within the controls (age range: 58 to 89 years; P[3H](-)nicotine = 0.002, P[3H]epibatidine = 0.010, P[3H]cytisine = 0.037). In the older controls, the [3H]epibatidine binding was much decreased as compared with that of [3H](-)nicotine and [3H]cytisine. This may indicate a higher selectivity of [3H]epibatidine for a nicotinic receptor subtype that is particularly affected by aging. The laminar binding pattern of [3H]vesamicol showed one maximum in the outer cortical layers II/III. The [3H]vesamicol binding did not change with aging. The binding of all ligands was significantly decreased in all layers of the temporal cortex in Alzheimer's disease, but the [3H]vesamicol binding decreased only half as much as the nicotinic receptors. Also, choline acetyltransferase activity was percentually more reduced than [3H]vesamicol binding in Alzheimer's disease. The cortical laminar binding pattern of all 3H-ligands was largely absent in the Alzheimer's disease cases. The less severe loss of vesicular acetylcholine transport sites as compared with the loss of the nicotinic receptors and choline acetyltransferase activity may suggest that vesamicol binding sites might be more preserved in presynaptic terminals still existing and thereby expressing compensatory capacity to maintain cholinergic activity.
ESTHER : Sihver_1999_Neurosci_94_685
PubMedSearch : Sihver_1999_Neurosci_94_685
PubMedID: 10579560

Title : Regional distribution of nicotinic receptor subunit mRNAs in human brain: comparison between Alzheimer and normal brain - Hellstrom-Lindahl_1999_Brain.Res.Mol.Brain.Res_66_94
Author(s) : Hellstrom-Lindahl E , Mousavi M , Zhang X , Ravid R , Nordberg A
Ref : Brain Research Mol Brain Res , 66 :94 , 1999
Abstract : The regional expression of mRNA for the nicotinic acetylcholine receptor (nAChR) subunits alpha3, alpha4 and alpha7 was examined in postmortem brain tissues from controls and patients with Alzheimer's disease (AD) by using quantitative RT-PCR. In parallel, the numbers of nAChRs were measured by receptor binding. Relative quantification of the nAChR gene transcripts in control brains showed that expression of alpha3 was highest in the parietal cortex, frontal cortex and hippocampus, and lower in the temporal cortex and cerebellum. The highest level of alpha4 mRNA was found in the temporal cortex and cerebellum, while alpha7 mRNA was equally distributed in all brain regions except for hippocampus where it was less abundant. In comparison with AD brains, no differences in the expression of alpha3 and alpha4 in the temporal cortex, hippocampus and cerebellum were found. The level of alpha7 mRNA was significantly higher in the hippocampus of AD brains compared to controls. The binding sites for [3H] epibatidine and [3H] nicotine in the temporal cortex and [125I] alpha-bungarotoxin in hippocampus were significantly decreased in AD patients compared to controls. Saturation analysis of [3H] epibatidine binding revealed two classes of binding sites, with a significant reduction of the higher affinity epibatidine binding sites in the temporal cortex of AD brain. The results show that there is a regional distribution of the expression of the different nAChRs subunits in human brain. The findings that the alpha3 and alpha4 mRNA levels were not changed in AD brains suggest that the loss of higher affinity epibatidine binding sites observed in AD patients cannot be attributed to alternations at the transcriptional level of the alpha3 and alpha4 genes and that causes have to be searched for at the translational and/or posttranslational level. The increased mRNA level of alpha7 previously found in lymphocytes, and now also in the hippocampus of AD patients, indicate that subunit specific changes in gene expression of nAChRs is associated with AD.
ESTHER : Hellstrom-Lindahl_1999_Brain.Res.Mol.Brain.Res_66_94
PubMedSearch : Hellstrom-Lindahl_1999_Brain.Res.Mol.Brain.Res_66_94
PubMedID: 10095081

Title : Beta-estradiol attenuate amyloid beta-peptide toxicity via nicotinic receptors - Svensson_1999_Neuroreport_10_3485
Author(s) : Svensson AL , Nordberg A
Ref : Neuroreport , 10 :3485 , 1999
Abstract : A number of epidemiological studies suggest that estrogen therapy is linked to a reduced risk of developing Alzheimer's disease (AD). The present study was conducted to evaluate the effect of 17beta-estradiol on beta-amyloid (Abeta)-induced toxicity and was performed in rat pheochromocytoma PC 12 cells by measuring the mitochondrial activity. 17Beta-estradiol (10(-5), 10(-6) and 10(-8) M) attenuated Abeta(25-35)-induced toxicity in PC 12 cells. The neuroprotective effect of 17beta-estradiol (10(-5) M) was prevented in the presence of the nicotinic antagonists methyllycaconitine (MLA) and mecamylamine, suggesting an interaction probably via the alpha7 nicotinic receptor subtype. Chronic treatment with 17beta-estradiol (10(-10)-10(-5) M) alone did not change the number of [3H]epibatidine binding sites in human neuroblastoma SH-SY5Y cells and rat PC 12 cells, but significantly prevented the enhanced [3H]epibatidine binding in nicotine-treated PC 12 cells. This study demonstrates that 17beta-estradiol exerts neuroprotective effects which might involve interaction with the alpha7 nicotinic receptor subtype.
ESTHER : Svensson_1999_Neuroreport_10_3485
PubMedSearch : Svensson_1999_Neuroreport_10_3485
PubMedID: 10619630

Title : Synthesis and characterization of binding of 5-[76Br]bromo-3-[[2(S)-azetidinyl]methoxy]pyridine, a novel nicotinic acetylcholine receptor ligand, in rat brain - Sihver_1999_J.Neurochem_73_1264
Author(s) : Sihver W , Fasth KJ , Horti AG , Koren AO , Bergstrom M , Lu L , Hagberg G , Lundqvist H , Dannals RF , London ED , Nordberg A , Langstrom B
Ref : Journal of Neurochemistry , 73 :1264 , 1999
Abstract : 5-[76Br]Bromo-3-[[2(S)-azetidinyl]methoxy]pyridine ([76Br]BAP), a novel nicotinic acetylcholine receptor ligand, was synthesized using [76Br]bromide in an oxidative bromodestannylation of the corresponding trimethylstannyl compound. The radiochemical yield was 25%, and the specific radioactivity was on the order of 1 Ci/micromol. The binding properties of [76Br]BAP were characterized in vitro and in vivo in rat brain, and positron emission tomography (PET) experiments were performed in two rhesus monkeys. In association experiments on membranes of the cortex and thalamus, >90% of maximal specific [76Br]BAP binding was obtained after 60 min. The dissociation half-life of [76Br]BAP was 51 +/- 6 min in cortical membranes and 56 +/- 3 min in thalamic membranes. Saturation experiments with [76Br]BAP revealed one population of binding sites with dissociation constant (K(D)) values of 36 +/- 9 and 30 +/- 9 pM in membranes of cortex and thalamus, respectively. The maximal binding site density (Bmax) values were 90 +/- 17 and 207 +/- 33 fmol/mg in membranes of cortex and thalamus, respectively. Scatchard plots were nonlinear, and the Hill coefficients were <1, suggesting the presence of a lower-affinity binding site. In vitro autoradiography studies showed that binding of [76Br]BAP was high in the thalamus and presubiculum, moderate in the cortex and striatum, and low in the cerebellum and hippocampus. A similar pattern of [76Br]BAP accumulation was observed by ex vivo autoradiography. In vivo, binding of [76Br]BAP in whole rat brain was blocked by preinjection of (S)(-)-nicotine (0.3 mg/kg) by 27, 52, 68, and 91% at survival times of 10, 25, 40, 120, and 300 min, respectively. In a preliminary PET study in rhesus monkeys, the highest [76Br]BAP uptake was found in the thalamus, and radioactivity was displaceable by approximately 60% with cytisine and by 50% with (S)(-)-nicotine. The data of this study indicate that [76Br]BAP is a promising radioligand for the characterization of nicotinic acetylcholine receptors in vivo.
ESTHER : Sihver_1999_J.Neurochem_73_1264
PubMedSearch : Sihver_1999_J.Neurochem_73_1264
PubMedID: 10461920

Title : Tacrine and donepezil attenuate the neurotoxic effect of A beta(25-35) in rat PC12 cells - Svensson_1998_Neuroreport_9_1519
Author(s) : Svensson AL , Nordberg A
Ref : Neuroreport , 9 :1519 , 1998
Abstract : The effect of the cholinesterase inhibitors tacrine and donepezil on A beta(25-35)-induced toxicity was investigated in rat pheochromocytoma PC12 cells by measuring the mitochondrial activity. Tacrine and donepezil was found in clinical relevant concentrations (10(-7)-10(-6) M) to attenuate A beta(25-35)-induced toxicity in PC12 cells. The neuroprotective effect of tacrine was blocked in the presence of the nicotinic antagonists mecamylamine (10(-5) M) and tubocurarine (10(-5) M), suggesting an interaction via nicotinic receptors. This study demonstrates that tacrine and donepezil can exert neuroprotective properties which might be of importance and contribute to the clinical efficacy of cholinesterase inhibitors in the treatment of Alzheimer's disease.
ESTHER : Svensson_1998_Neuroreport_9_1519
PubMedSearch : Svensson_1998_Neuroreport_9_1519
PubMedID: 9631459

Title : Nicotine exposure during a critical period of development leads to persistent changes in nicotinic acetylcholine receptors of adult rat brain - Miao_1998_J.Neurochem_70_752
Author(s) : Miao H , Liu C , Bishop K , Gong ZH , Nordberg A , Zhang X
Ref : Journal of Neurochemistry , 70 :752 , 1998
Abstract : Effects of neonatal nicotine exposure on the development of nicotinic acetylcholine receptor (nAChR) alpha2, alpha3, alpha4, alpha7, and beta2 subunit mRNAs and the number of nAChR isoforms in rat brain were studied. The mRNA levels for nAChR subunits were measured by ribonuclease protection assay, and the number of nAChR isoforms was measured with (-)-[3H]nicotine, [3H]epibatidine, and alpha-[3H]bungarotoxin ([3H]alpha-Bgt). Pups were divided into two groups: One group received (-)-nicotine treatment (0.1 mg/kg s.c. free base twice per day) during postnatal day (P)1 to P21 and the other during P8 to P16. The period from P8 to P16 was chosen due to persistent changes that occur in brain nAChRs and in the behavior of adult mice that received (-)-nicotine treatment during P10 to P16. (-)-Nicotine exposure from P1 to P21 significantly up-regulated the number of [3H]epibatidine and high-affinity (-)-[3H]nicotine binding sites in most of the brain regions studied but did not influence the number of [3H]alpha-Bgt binding sites. This effect was a transient one: The up-regulated binding sites returned to control level 1 week after withdrawal from nicotine. (-)-Nicotine exposure during P8 to P16 resulted in a significant and long-lasting increase in the number of nAChR isoforms labeled by (-)-[3H]nicotine, but not by [3H]epibatidine, in the cortex, hippocampus, and striatum of adult rat. This treatment converted the low-affinity binding sites of (-)-nicotine into a high-affinity state revealed by the competition studies of (-)-[3H]nicotine/(-)-nicotine. No changes in the mRNA levels of the subunits studied were observed following nicotine treatment during these two periods. These results suggest that the second postnatal week is a critical period during which nicotine treatment can induce permanent effects on the nAChRs in rat brain. The underlying mechanisms involved in the up-regulation of the number of nAChRs observed in this study are posttranscriptional.
ESTHER : Miao_1998_J.Neurochem_70_752
PubMedSearch : Miao_1998_J.Neurochem_70_752
PubMedID: 9453571

Title : Laminar distribution of nicotinic receptor subtypes in human cerebral cortex as determined by [3H](-)nicotine, [3H]cytisine and [3H]epibatidine in vitro autoradiography - Sihver_1998_Neurosci_85_1121
Author(s) : Sihver W , Gillberg PG , Nordberg A
Ref : Neuroscience , 85 :1121 , 1998
Abstract : The subregional localization of different nicotinic acetylcholine receptor subtypes in human cerebral cortex was estimated by quantitative in vitro autoradiography using the nicotinic ligands [3H](-)nicotine, [3H]cytisine and [3H]epibatidine in large whole human forebrain hemispheres. Saturation experiments in frontal cortex revealed for [3H](-)nicotine two binding sites with affinity constants (Kd) of 0.45 and 6.3 nM and binding site densities (Bmax) of 3.0 and 14.2 pmol/g, for [3H]cytisine one binding site with Kd of 0.19 nM and Bmax of 21.8 pmol/g, and for [3H]epibatidine one binding site with Kd of 0.011 nM and Bmax of 20.0 pmol/g. The laminar binding distributions of the three ligands were compared in different cortical areas by creating binding profiles perpendicular to the entire cortical depth. The regional autoradiographic binding patterns of the three ligands were essentially similar, with higher receptor binding in cortical layers I, III and V. In the primary sensory cortex and inferior frontal sulcus, marked binding of all ligands was observed in layer III. [3H]Cytisine showed the lowest difference between maximal and minimal binding within the gray tissue in all other areas. In the primary motor cortex, [3H]epibatidine and [3H](-)nicotine showed high binding in layers III and V. The [3H](-)nicotine binding was higher than that of the other ligands in layers I and VI of the primary motor cortex, the deeper layer V of the primary sensory cortex, layer III of the superior temporal sulcus and layer VI of the parietal cortex. A distinct band of binding of [3H](-)nicotine and [3H]epibatidine but not of [3H]cytisine was found in layer IIlb of the occipital cortex and layer V of the superior temporal sulcus. [3H]Epibatidine showed higher binding than the other ligands in all layers of the medial frontal, superior frontal and superior temporal sulcus. The findings with the three nicotinic ligands suggest three binding sites in the cortex with different laminar distributions. All three ligands bound to an identical receptor site, most likely the alpha4 nicotinic receptor subunit. The morphological distribution of [3H]epibatidine and [3H](-)nicotine binding indicate that they bind to an additional site, especially in the primary motor cortex, in layer IIIb of the occipital cortex and layer V of the superior temporal sulcus. High binding of [3H](-)nicotine in layers I and VI of the primary motor cortex, the deeper layer V of the primary sensory cortex, layer III of the superior temporal sulcus and layer VI of the parietal cortex may indicate a third binding site.
ESTHER : Sihver_1998_Neurosci_85_1121
PubMedSearch : Sihver_1998_Neurosci_85_1121
PubMedID: 9681951

Title : Long-term tacrine treatment in three mild Alzheimer patients: effects on nicotinic receptors, cerebral blood flow, glucose metabolism, EEG, and cognitive abilities - Nordberg_1998_Alzheimer.Dis.Assoc.Disord_12_228
Author(s) : Nordberg A , Amberla K , Shigeta M , Lundqvist H , Viitanen M , Hellstrom-Lindahl E , Johansson M , Andersson J , Hartvig P , Lilja A , Langstrom B , Winblad B
Ref : Alzheimer Disease & Associated Disorders , 12 :228 , 1998
Abstract : The effect of long-term treatment with tacrine (tetrahydroaminoacridine) was studied in three Alzheimer patients (aged 57, 64, and 68 years) with mild dementia. All three patients had a Mini-Mental State Examination score of 24/30 and carried at least one apolipoprotein E (ApoE) epsilon4 allele. Tacrine was given in doses between 80 and to 160 mg daily for 13-31 months. A lower tacrine concentration was observed generally in cerebrospinal fluid (CSF) compared with plasma. The acetylcholinesterase activity in CSF tended to be increased following longer periods of tacrine treatment, whereas the butyrylcholinesterase activity was decreased. The three patients repeatedly underwent positron emission tomography investigation of cerebral blood flow, nicotinic receptors, cerebral glucose metabolism, and electroencephalogram (EEG) and cognitive tests. Positive influences on these parameters were observed following both short-term and long-term treatment with tacrine. Improvement of nicotinic receptors (measured as 11C-nicotine binding), cerebral blood flow, EEG, and some cognitive tests (trail making test, block design test) occurred earlier after initiation of tacrine treatment compared with the glucose metabolism, which was increased after several months of tacrine treatment. An improvement in attention (trail making test) was observed following tacrine as sign for frontal lobe activation (EEG). The functional effects of tacrine in Alzheimer patients appeared to be related to both dose and length of cholinesterase inhibitor treatment.
ESTHER : Nordberg_1998_Alzheimer.Dis.Assoc.Disord_12_228
PubMedSearch : Nordberg_1998_Alzheimer.Dis.Assoc.Disord_12_228
PubMedID: 9772028

Title : Cholinesterase inhibitors in the treatment of Alzheimer's disease: a comparison of tolerability and pharmacology - Nordberg_1998_Drug.Saf_19_465
Author(s) : Nordberg A , Svensson AL
Ref : Drug Safety , 19 :465 , 1998
Abstract : Cholinesterase inhibitors are currently the most established treatment strategy in Alzheimer's disease. The treatment effect appears mainly to be symptomatic. Effects on progression of the disease following long term treatment, and possible neuroprotective effects, have been investigated. Delay until nursing home placement has been reported. Three cholinesterase inhibitors, tacrine, donepezil and rivastigmine, are in clinical use. Other cholinesterase inhibitors, such as galantamine (galanthamine), metrifonate, physostigmine, eptastigmine, are currently under clinical evaluation. So far the efficacy appears to be comparable between the various cholinesterase inhibitors; treatment for up to 6 months has produced an improvement in Alzheimer's Disease Assessment Scale -- Cognitive Subscale score (ADAS-cog) of between 1.8 and 4.9 in patients with Alzheimer's disease. Tacrine, donepezil, galantamine and physostigmine are reversible inhibitors of acetylcholinesterase and butyrylcholinesterase, while metrifonate is considered to be an irreversible inhibitor and rivastigmine a pseudoirreversible inhibitor. Tacrine and physostigmine have lower bioavailability, 17 to 37% and 3 to 8%, respectively, than the other cholinesterase inhibitors such as rivastigmine, galantamine and donepezil (40 to 100%). The elimination half-life is considerably longer for donepezil (70 to 80h) in comparison to most of the other cholinesterase inhibitors (0.3 to 12h). Donepezil is therefore administered once daily in comparison to rivastigmine which is administered twice daily and tacrine which is administered 4 times daily. Simultaneous food intake lowers the plasma concentration of tacrine and reduces the adverse effects of rivastigmine. Drugs like theophylline and cimetidine have been reported to change the pharmacokinetics of tacrine and donepezil. In contrast, concomitant medication with various drugs with rivastigmine does not seem to cause any drug interactions in patients with Alzheimer's disease. Tacrine, donepezil and galantamine are metabolised via the cytochrome P450 (CYP) liver enzymes. Active metabolites are known for tacrine and galantamine. Rivastigmine is not metabolised via CYP enzymes, but via esterases and is excreted in the urine. Tacrine is associated with hepatotoxicity while other cholinesterase inhibitors seem devoid this adverse effect. Increased liver enzyme values have been observed in 49% of patients with Alzheimer's disease treated with tacrine. Rechallenge with tacrine reduces the incidence of elevated liver enzyme levels. Peripheral cholinergic adverse effects are common for the cholinesterase inhibitors, with an incidence ranging between 7 to 30%. For some cholinesterase inhibitors, such as rivastigmine, the cholinergic adverse effects such as nausea, vomiting, dizziness, diarrhoea and abdominal pain can be reduced by slowing the rate of dose titration.
ESTHER : Nordberg_1998_Drug.Saf_19_465
PubMedSearch : Nordberg_1998_Drug.Saf_19_465
PubMedID: 9880090

Title : Regulation of nicotinic receptor subtypes following chronic nicotinic agonist exposure in M10 and SH-SY5Y neuroblastoma cells - Warpman_1998_J.Neurochem_70_2028
Author(s) : Warpman U , Friberg L , Gillespie A , Hellstrom-Lindahl E , Zhang X , Nordberg A
Ref : Journal of Neurochemistry , 70 :2028 , 1998
Abstract : The present study further investigated whether nicotinic acetylcholine receptor (nAChR) subtypes differ in their ability to up-regulate following chronic exposure to nicotinic agonists. Seven nicotinic agonists were studied for their ability to influence the number of chick alpha4beta2 nAChR binding sites stably transfected in fibroblasts (M10 cells) following 3 days of exposure. The result showed a positive correlation between the Ki values for binding inhibition and EC50 values for agonist-induced alpha4beta2 nAChR up-regulation. The effects of epibatidine and nicotine were further investigated in human neuroblastoma SH-SY5Y cells (expressing alpha3, alpha5, beta2, and beta4 nAChR subunits). Nicotine exhibited a 14 times lower affinity for the nAChRs in SH-SY5Y cells as compared with M10 cells, whereas epibatidine showed similar affinities for the nAChRs expressed in the two cell lines. The nicotine-induced up-regulation of nAChR binding sites in SH-SY5Y cells was shifted to the right by two orders of magnitude as compared with that in M10 cells. The epibatidine-induced up-regulation of nAChR binding sites in SH-SY5Y cells was one-fourth that in M10 cells. The levels of mRNA of the various nAChR subunits were measured following the nicotinic agonist exposure. In summary, the various nAChR subtypes show different properties in their response to chronic stimulation.
ESTHER : Warpman_1998_J.Neurochem_70_2028
PubMedSearch : Warpman_1998_J.Neurochem_70_2028
PubMedID: 9572289

Title : Chronic ethanol treatment decreases [3H]epibatidine and [3H]nicotine binding and differentially regulates mRNA levels of nicotinic acetylcholine receptor subunits expressed in M10 and SH-SY5Y neuroblastoma cells - Gorbounova_1998_J.Neurochem_70_1134
Author(s) : Gorbounova O , Svensson AL , Jonsson P , Mousavi M , Miao H , Hellstrom-Lindahl E , Nordberg A
Ref : Journal of Neurochemistry , 70 :1134 , 1998
Abstract : For a study of the underlying mechanisms of a possible interaction between ethanol and nicotinic receptors during ethanol dependence, the aim of this work was to investigate the effect of chronic ethanol exposure on nicotinic receptor subtypes in a transfected fibroblast cell line (M10 cells) stably expressing alpha4beta2 nicotinic receptor subtype and an SH-SY5Y neuroblastoma cell line expressing alpha3, alpha5, alpha7, beta2, and beta4 nicotinic acetylcholine receptor (nAChR) subunits. A significant dose-related decrease (-30-80%) in number of [3H]nicotine binding sites was observed in ethanol-treated (25-240 mM) compared with untreated M10 cells. Similarly, 4-day treatment with ethanol in concentrations relevant to chronic alcoholism (100 mM) decreased the number of nicotinic receptor binding sites in the SH-SY5Y cells when measured using [3H]epibatidine. When M10 cells were chronically treated with nicotine, ethanol partly inhibited the up-regulation of nicotinic receptors when present in the cells together with nicotine. Chronic treatment for 4 days with 100 mM ethanol significantly decreased the mRNA level for the alpha3 nAChR subunit (-39%), while the mRNA levels for the alpha7 (+30%) and alpha4 (+22%) subunits were significantly increased. Chronic ethanol treatment did not affect the mRNA levels for the beta2 nAChR subunit. Changes in the levels of nAChR protein and mRNA may have adaptive significance and be involved in the development of dependence, tolerance, and addiction to chronic ethanol and nicotine exposure. They also may be targets for therapeutic strategies in the treatment of ethanol and nicotine dependence.
ESTHER : Gorbounova_1998_J.Neurochem_70_1134
PubMedSearch : Gorbounova_1998_J.Neurochem_70_1134
PubMedID: 9489734

Title : Postnatal changes of nicotinic acetylcholine receptor alpha 2, alpha 3, alpha 4, alpha 7 and beta 2 subunits genes expression in rat brain - Zhang_1998_Int.J.Dev.Neurosci_16_507
Author(s) : Zhang X , Liu C , Miao H , Gong ZH , Nordberg A
Ref : Int J Developmental Neuroscience , 16 :507 , 1998
Abstract : Postnatal changes of nicotinic acetylcholine receptor (nAChR) alpha 2, alpha 3, alpha 4, alpha 7 and beta 2 subunits mRNAs were investigated in rat brain using ribonuclease protection assay. Multiple developmental patterns were observed: (1) transient expression during the first few postnatal weeks; alpha 2 in the hippocampus and brain stem, alpha 3 in the striatum, cerebellum and cortex, alpha 4 in the hippocampus, striatum and cerebellum, alpha 7 in the cerebellum and beta 2 in the striatum. (2) Constant expression across development; alpha 2 and alpha 3 in the thalamus, alpha 4 in the cortex, thalamus and brain stem, alpha 7 in the thalamus and brain stem and beta 2 in all brain regions except striatum. (3) Non-detection across development; alpha 2 in the cortex, striatum and cerebellum. (4) Increase with age; alpha 7 in the cortex and hippocampus. (5) Bell-shaped development; alpha 7 in the striatum. Postnatal changes of nAChR isoforms in different brain regions of rat were investigated by receptor binding assays. The developmental patterns of [3H]epibatidine and (-)-[3H]nicotine binding sites were similar to each other in each brain region, but different from that of [3H] alpha-bungarotoxin binding sites. No obvious correlation was observed between the developmental patterns of [3H] alpha-bungarotoxin, [3H]epibatidine and (-)-[3H]nicotine binding sites and corresponding subunits mRNAs. These results indicate that multiple mechanisms are involved in changes of gene expression of nAChRs subunits in the brain of developing rats.
ESTHER : Zhang_1998_Int.J.Dev.Neurosci_16_507
PubMedSearch : Zhang_1998_Int.J.Dev.Neurosci_16_507
PubMedID: 9881299

Title : Longitudinal changes in quantitative EEG during long-term tacrine treatment of patients with Alzheimer's disease - Jelic_1998_Neurosci.Lett_254_85
Author(s) : Jelic V , Dierks T , Amberla K , Almkvist O , Winblad B , Nordberg A
Ref : Neuroscience Letters , 254 :85 , 1998
Abstract : Quantitative EEG is a potentially useful tool in demonstrating the effects of treatments with acetylcholinesterase (AChE) inhibitors on the progression of Alzheimer's disease (AD). In order to define the profile of EEG changes during tacrine long-term treatment, for 12 months we followed 15 AD patients receiving an optimal individually tolerable dose. After 3 months theta global field power (GFP) was significantly reduced, and after 6 months both theta and delta GFP decreased. Theta GFP was still reduced after 12 months of treatment when compared to the baseline. Significant decreases in fast activities of beta 1 and beta 2 GFP were also observed. The untreated reference group (n = 10) did not show any significant changes in GFP after 12 months follow-up, although generators of theta activity had a significant shift towards posterior regions. These findings suggest that slowing in fast EEG frequencies during chronic treatment with AChE inhibitors may provide an early indicator of declining treatment efficiency.
ESTHER : Jelic_1998_Neurosci.Lett_254_85
PubMedSearch : Jelic_1998_Neurosci.Lett_254_85
PubMedID: 9779926

Title : Modulation of dopamine release by the nicotinic agonist epibatidine in the frontal cortex and the nucleus accumbens of naive and chronic nicotine treated rats -
Author(s) : Friberg L , Bednar I , Nordberg A
Ref : Journal de Physiologie (Paris) , 92 :431 , 1998
PubMedID:

Title : Regional distribution of nicotinic receptors during prenatal development of human brain and spinal cord - Hellstrom-Lindahl_1998_Brain.Res.Dev.Brain.Res_108_147
Author(s) : Hellstrom-Lindahl E , Gorbounova O , Seiger A , Mousavi M , Nordberg A
Ref : Brain Research Developmental Brain Research , 108 :147 , 1998
Abstract : The development of nicotinic acetylcholine receptors (nAChRs) in brains from human fetuses of 4-12 weeks gestational age was studied. The expression of nAChR subunit mRNAs was analyzed using reverse transcriptase-polymerase chain reaction. Expression of alpha 3, alpha 4, alpha 5, alpha 7, beta 2, beta 3 and beta 4 mRNA were all detected in the prenatal spinal cord, medulla oblongata, pons, cerebellum, mesencephalon, subcortical forebrain and cortex during first trimester development. Relative quantification of mRNA showed that the highest levels for alpha 3, alpha 4 and alpha 7 were expressed in the spinal cord, alpha 5 was most abundant in the cortex and beta 3 was highest in the cerebellum. beta 4 seemed to be equally distributed in all regions whereas beta 2 was high in the cortex and cerebellum. A comparison of expression of nAChR subunit mRNAs in the cortex and cerebellum of prenatal and aged (54-81 years) brain showed that mRNA levels for alpha 4, alpha 5, alpha 7, beta 2 and beta 4 were significantly higher in the prenatal cortex and cerebellum than in aged brain, whereas the level of alpha 3 transcript was similar, and beta 3 significantly higher in aged cortex. Specific binding of [3H]-epibatidine to prenatal brain membranes was detected as early as 4-5 weeks of gestation in the spinal cord, medulla oblongata, pons and subcortical forebrain. A positive correlation between gestational age and [3H]-epibatidine and [3H]-cytisine binding was found in several brain regions. The highest specific binding of [3H]-epibatidine and [3H]-cytisine was detected in the spinal cord, pons and medulla oblongata and the lowest in the cortex. Saturation analysis of [3H]-cytisine binding in both prenatal and aged brain were best fit by a model for a single site, whereas binding data for [3H]-epibatidine revealed two classes of binding sites. The early presence of nAChR proteins and gene transcripts shown in the present study suggests an important role for nAChRs in modulating dendritic outgrowth, establishment of neuronal connections and synaptogenesis during development.
ESTHER : Hellstrom-Lindahl_1998_Brain.Res.Dev.Brain.Res_108_147
PubMedSearch : Hellstrom-Lindahl_1998_Brain.Res.Dev.Brain.Res_108_147
PubMedID: 9693793

Title : Expression of nicotinic receptor alpha and beta subunits in the prenatal and aged human brain -
Author(s) : Hellstrom-Lindahl E , Gorbounova O , Seiger A , Mousavi M , Nordberg A
Ref : Journal de Physiologie (Paris) , 92 :438 , 1998
PubMedID:

Title : Regulation of nicotinic receptors in the brain of mice withdrawn from chronic oral nicotine treatment - Pietila_1998_Naunyn.Schmiedebergs.Arch.Pharmacol_357_176
Author(s) : Pietila K , Lahde T , Attila M , Ahtee L , Nordberg A
Ref : Naunyn Schmiedebergs Arch Pharmacol , 357 :176 , 1998
Abstract : The effect of nicotine withdrawal on regional regulation of brain nicotinic receptors was studied in mice after chronic administration of nicotine in the drinking water for 2, 4 or 7 weeks. Two weeks of chronic nicotine administration did not alter the binding of [3H]-nicotine in the midbrain, cortex or cerebellum of the mice, while after both 4-and 7-week treatments a significant increase in the specific [3H]-nicotine binding was observed in cortical and midbrain membranes. In the midbrain, the [3H]-nicotine binding was increased by about 40% in mice withdrawn for 48-72 h from the 4-week chronic nicotine treatment and in mice withdrawn for 48 h from the 7-week treatment. The [3H]-nicotine binding was significantly increased (by 55-65%) in the cortex at 48 h and 72 h after withdrawal from 4-week chronic nicotine and it was even somewhat more increased (by 72-66%) after 7-week treatment. The cortical [3H]-nicotine binding was not altered at 24 h after the 4-week treatment, but in mice withdrawn for 24 h from the 7-week treatment it was increased by 116%. The increases in [3H]-nicotine binding returned to control levels within 1 week after withdrawal. None of the studied treatments affected the [3H]-nicotine binding in the cerebellum. Tolerance towards nicotine-induced locomotor depression was only found in mice withdrawn for 24 h from the 7-week chronic nicotine administration. These findings suggest that at least 4-week chronic nicotine administration in the drinking water is needed before any upregulation of nicotinic receptors can be observed. Furthermore, in our experiments the increase in the [3H]-nicotine binding was seen before behavioural tolerance could be demonstrated. The differences between brain regions in the time course of nicotinic receptor upregulation may reflect variations in nicotinic receptor subunits and their sensitivity to chronic nicotine treatment.
ESTHER : Pietila_1998_Naunyn.Schmiedebergs.Arch.Pharmacol_357_176
PubMedSearch : Pietila_1998_Naunyn.Schmiedebergs.Arch.Pharmacol_357_176
PubMedID: 9521491

Title : Imaging of nicotinic and muscarinic receptors in Alzheimer's disease: effect of tacrine treatment - Nordberg_1997_Dement.Geriatr.Cogn.Disord_8_78
Author(s) : Nordberg A , Lundqvist H , Hartvig P , Andersson J , Johansson M , Hellstrom-Lindahl E , Langstrom B
Ref : Dementia & Geriatric Cognitive Disorders , 8 :78 , 1997
Abstract : Functional imaging techniques offer new possibilities for further understanding of changes in functional correlates of structural and biological changes in dementia disorders like Alzheimer's disease (AD). Regional disturbances in glucose metabolism and cerebral blood flow are known to occur in AD brains and probably roughly correlate to changes in neurotransmitter activities. A proper estimate would be to visualize the neuroreceptors themselves. In this study the cholinergic nicotinic and muscarinic receptors were studied in brain by positron emission tomography (PET). The rate constant k2* (s) (-)11C-nicotine was significantly higher (+43%) in temporal cortex of AD patients compared to controls (p < 0.017) indicating a lower binding of 11C-nicotine in AD brains compared to controls. Treatment with the cholinesterase inhibitor tacrine (80 mg daily) during 3 months to AD patients resulted in a mean plasma concentration of 7.7 +/- 0.8 ng/ml and a corresponding inhibition of the cholinesterase activity in plasma by 34 +/- 5%. A significantly lower k2* (increased binding) for 11C-nicotine binding (-15%; p < 0.006) was obtained in the temporal cortex after 3 months of treatment compared to prior treatment. The muscarinic antagonist 11C-benztropine was used to visualize muscarinic receptors and the binding capacity of 11C-benztropine (KR) was found to be decreased in the temporal cortex after 3 months of tacrine treatment.
ESTHER : Nordberg_1997_Dement.Geriatr.Cogn.Disord_8_78
PubMedSearch : Nordberg_1997_Dement.Geriatr.Cogn.Disord_8_78
PubMedID: 9065319

Title : Nicotinic receptors, muscarinic receptors and choline acetyltransferase activity in the temporal cortex of Alzheimer patients with differing apolipoprotein E genotypes - Svensson_1997_Neurosci.Lett_232_37
Author(s) : Svensson AL , Warpman U , Hellstrom-Lindahl E , Bogdanovic N , Lannfelt L , Nordberg A
Ref : Neuroscience Letters , 232 :37 , 1997
Abstract : The number of nicotinic and muscarinic receptors and choline acetyltransferase (ChAT) activity were investigated in the temporal cortex of patients with Alzheimer's disease (AD) with different apolipoprotein E (APOE) genotypes. A significant reduction in the ChAT activity (P < 0.001) and in the number of nicotinic receptors (P < 0.001) was observed in the temporal cortex of AD brains independent of APOE genotype. The number of muscarinic receptors were unchanged in AD brains compared to control in both epsilon 4 and epsilon 3 carriers. A significant negative correlation (P < 0.001) was observed in AD brains between the histopathological dementia score and ChAT activity, which was independent of the APOE genotype. In this study the presence of the APOE epsilon 4 allele was not related to specific deficits in cholinergic activity in the temporal cortex of AD brains.
ESTHER : Svensson_1997_Neurosci.Lett_232_37
PubMedSearch : Svensson_1997_Neurosci.Lett_232_37
PubMedID: 9292886

Title : Treatment of Alzheimer disease with tacrine: a cost-analysis model - Wimo_1997_Alzheimer.Dis.Assoc.Disord_11_191
Author(s) : Wimo A , Karlsson G , Nordberg A , Winblad B
Ref : Alzheimer Disease & Associated Disorders , 11 :191 , 1997
Abstract : In a cost-analysis model, the effect on the costs of Alzheimer disease of tacrine (tetrahydroaminoacridine) treatment was studied. A model of the survival of the Swedish Alzheimer disease population was constructed in which the placement of patients with Alzheimer disease in care organization was assumed to be influenced by the use of tacrine. Based on this model, the cost analysis was performed. Fifty-two percent of the Alzheimer disease population with an initial Mini-Mental State Examination (MMSE) score of 10 to 24 points are in the main alternative of the model treated with 160 mg tacrine with an initial improvement in MMSE of 2.6 points. The benefit of tacrine was a cost reduction of 1.3% when the results were calculated for the entire Alzheimer disease population. This corresponds to a benefit of 1.3 billion Swedish kronor (SEK) (with 3% discount rate) for the entire estimated survival period. The annual benefit per patient was estimated as 2,900 SEK [approximately U.S. $320 (1993)]. In the sensitivity analysis, the range was between -0.6% and 5.2%. Beginning treatment in the early stages of Alzheimer disease results in lower costs than a later start. The main conclusion is that tacrine, according to the model, has beneficial but modest effects on the costs of Alzheimer disease in Sweden.
ESTHER : Wimo_1997_Alzheimer.Dis.Assoc.Disord_11_191
PubMedSearch : Wimo_1997_Alzheimer.Dis.Assoc.Disord_11_191
PubMedID: 9437436

Title : Biphasic effect of tacrine on acetylcholine release in rat brain via M1 and M2 receptors - Svensson_1996_Brain.Res_726_207
Author(s) : Svensson AL , Zhang X , Nordberg A
Ref : Brain Research , 726 :207 , 1996
Abstract : Rat cortical synaptosomes preloaded with [3H]choline were superfused and stimulated with K+ in order to investigate the effect of the cholinesterase inhibitor tacrine on the in vitro release of acetylcholine (ACh). Tacrine was found to biphasically both increase (10(-6) and 5 x 10(-6) M) and decrease (10(-5)-10(-4) M) the release of ACh in a concentration-dependent manner. The facilitatory effect of tacrine was prevented by atropine and the M1 antagonist pirenzepine, whereas the inhibitory effect induced by tacrine was blocked by atropine and the M2 antagonist AF-DX 116. These results indicate that tacrine causes a biphasic effect on K+ stimulated ACh release in the brain via M1 and M2 muscarinic receptors. The tacrine induced enhancement of the ACh release occurs at clinical relevant tacrine concentrations and might therefore be of importance for the treatment outcome of Alzheimer's disease.
ESTHER : Svensson_1996_Brain.Res_726_207
PubMedSearch : Svensson_1996_Brain.Res_726_207
PubMedID: 8836562

Title : Functional studies of new drugs for the treatment of Alzheimer's disease - Nordberg_1996_Acta.Neurol.Scand.Suppl_165_137
Author(s) : Nordberg A
Ref : Acta Neurologica Scandinavica Supplementum , 165 :137 , 1996
Abstract : Few treatments for Alzheimer's disease (AD) have been evaluated to date by studying their effects on functional brain activity. Neuroimaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) are important tools that can provide an increased understanding of functional correlates to biological and structural changes in brains of patients with AD. These techniques provide valuable information about effects of drug treatments on functional parameters including blood flow, glucose metabolism, and neurotransmitter activity. Functional study outcomes are especially valuable when they are combined with studies of the effect of treatment on EEG and cognitive tests. This paper discusses functional changes observed in the brains of patients with AD following treatment with tacrine or nerve growth factor. Although these agents represent different approaches to cognitive drug treatment for AD, functional study outcomes indicate that both drugs improve cholinergic activity in the brain during long-term treatment.
ESTHER : Nordberg_1996_Acta.Neurol.Scand.Suppl_165_137
PubMedSearch : Nordberg_1996_Acta.Neurol.Scand.Suppl_165_137
PubMedID: 8741001

Title : Pharmacological treatment of cognitive dysfunction in dementia disorders - Nordberg_1996_Acta.Neurol.Scand.Suppl_168_87
Author(s) : Nordberg A
Ref : Acta Neurologica Scandinavica Supplementum , 168 :87 , 1996
Abstract : Dementia represents a complex heterogeneity of disorders. For Alzheimer's disease great progress in the understanding of underlying genetical, neuropathological and neurochemical mechanisms of the disease has been made during recent years. A variety of therapeutic approaches with cognitive enhancing drugs have been tested in Alzheimer patients. Presently, four main treatment strategies prevail, namely transmitter replacement therapy, growth factors, anti-inflammatory drugs and drugs affecting amyloid processing in the brain. The transmitter therapy is so far the most explored and fruitful strategy. The cholinesterase inhibitor tacrine is in clinical use in many countries. Other cholinergic treatment strategies than cholinesterase inhibitors in development are selective muscarinic receptor agonists and nicotine receptor agonists. The selective 5HT re-uptake blockers might be complementary to drugs with more specific effect on cognition. Although treatment with growth factor therapy e.g. nerve growth factor in Alzheimer patients has given some promising results, further research is needed. Development of drugs affecting amyloid processing is still mainly on a preclinical level.
ESTHER : Nordberg_1996_Acta.Neurol.Scand.Suppl_168_87
PubMedSearch : Nordberg_1996_Acta.Neurol.Scand.Suppl_168_87
PubMedID: 8997426

Title : [More accurate diagnosis could identify patients suitable for tacrine therapy] -
Author(s) : Andreasen N , Eriksson S , Karlsson I , Lindahl B , Lund M , Nordberg A , Wimo A , Winblad B , Astrand R
Ref : Lakartidningen , 93 :1200 , 1996
PubMedID: 8656831

Title : Muscarinic receptor subtypes in subpopulations of human blood mononuclear cells as analyzed by RT-PCR technique - Hellstrom-Lindahl_1996_J.Neuroimmunol_68_139
Author(s) : Hellstrom-Lindahl E , Nordberg A
Ref : Journal of Neuroimmunology , 68 :139 , 1996
Abstract : In this study we have analysed the expression of mRNA encoding the m1-m5 mAChR subtypes in human blood mononuclear cells and subpopulations of lymphocytes using reverse transcriptase-polymerase chain reaction (RT-PCR) technique. Total RNA was extracted from human blood mononuclear cells. T cells, monocytes. EB virus transformed B cells and from two leukemic cell lines and analysed by RT-PCR. Our results indicate that mRNAs for the m3, m4 and m5 muscarinic subtypes are expressed in mononuclear cells and purified T cells while m1 and m2 mRNAs were not detected in these cells. No m1-m5 subtype mRNA was detected in B cells and monocytes, indicating absence of muscarinic receptors in these cells. The expression of muscarinic subtypes in the leukemic T cell line. Peer, and the promyelocytic leukemic cell line HL-60 was different from peripheral mononuclear cells. Both m3 and m5 subtypes were expressed in Peer cells but not the m4 subtype, whereas the m4 and m5 subtypes detected in HL-60 cells.
ESTHER : Hellstrom-Lindahl_1996_J.Neuroimmunol_68_139
PubMedSearch : Hellstrom-Lindahl_1996_J.Neuroimmunol_68_139
PubMedID: 8784270

Title : Tacrine interacts with an allosteric activator site on alpha 4 beta 2 nAChRs in M10 cells - Svensson_1996_Neuroreport_7_2201
Author(s) : Svensson AL , Nordberg A
Ref : Neuroreport , 7 :2201 , 1996
Abstract : The effect of chronic treatment with the cholinesterase inhibitor tacrine on alpha 4 beta 2 nicotinic acetylcholine receptors (nAChRs) was investigated in a transfected fibroblast cell line, M10. Tacrine significantly increased (+46%; 5 x 10(-8) to 10(-5) M) and decreased (-74%; 2 x 10(-5) to 10(-4) M) the number of nAChRs in the M10 cells in a concentration-dependent manner when using [3H]cytisine as labelled ligand. The mRNA levels for alpha 4 or beta 2 nAChR subunits remained unchanged following the treatment. The tacrine-induced increase in number of nAChRs was significantly blocked by the antagonist mecamylamine (10(-4) M), while tubocurarine (10(-4) M) had no effect. Neither of the antagonists prevented the decrease in the number of nAChRs obtained at the higher concentration of tacrine. Similar to nicotine, tacrine (5 x 10(-5) M) decreased the turnover rate of nAChRs, which might indicate neuroprotective properties. This study demonstrates that tacrine interacts with two sites on nAChRs, where activation of the noncompetitive allosteric site might contribute to the clinical efficacy of tacrine treatment in AD patients.
ESTHER : Svensson_1996_Neuroreport_7_2201
PubMedSearch : Svensson_1996_Neuroreport_7_2201
PubMedID: 8930989

Title : Steady-state pharmacokinetics of tacrine in long-term treatment of Alzheimer patients - Johansson_1996_Dementia_7_111
Author(s) : Johansson M , Hellstrom-Lindahl E , Nordberg A
Ref : Dementia , 7 :111 , 1996
Abstract : The pharmacokinetics of the cholinesterase inhibitor tacrine was studied in 5 Alzheimer patients during 12-31 months of treatment. A mean average steady-state concentration in plasma ranging from 1.1 to 30 ng/ml was obtained with doses ranging from 40 to 160 mg of tacrine daily. During treatment with 80 mg daily a maximal plasma concentration of tacrine (8.7 +/- 0.6 ng/ml) was obtained 1.3 +/- 0.2 h after intake of the morning dose. The mean elimination half-life was estimated at 5-7 h and remained unchanged when the tacrine dose was increased. The plasma concentration of tacrine was stable during long-term treatment with tacrine and no tolerance was observed regarding its cholinesterase inhibitory effect. A maximal 40% inhibition of plasma cholinesterase (ChE) activity and 60% inhibition of acetylcholinesterase activity in red blood cells was measured following treatment with the highest dose of 160 mg tacrine daily. A significant correlation was obtained between the plasma concentration of tacrine and the inhibition of ChE activity (p < 0.001). The tacrine concentration in CSF was measured in each patient on 1-3 occasions during the treatment and the ratio CSF/plasma concentration was estimated to be 0.47 +/- 0.09 (n = 11).
ESTHER : Johansson_1996_Dementia_7_111
PubMedSearch : Johansson_1996_Dementia_7_111
PubMedID: 8866685

Title : Differential co-expression of nicotinic acetylcholine receptor alpha 4 and beta 2 subunit genes in various regions of rat brain - Liu_1996_Neuroreport_7_1645
Author(s) : Liu C , Nordberg A , Zhang X
Ref : Neuroreport , 7 :1645 , 1996
Abstract : The predominant nicotinic acetylcholine receptor (nAChR) subtype in brain binds nicotine with high affinity and has an alpha 4:beta 2 subunit stoichiometry of 2:3. In this study, the mRNA levels of nAChR alpha 4 and beta 2 subunits were simultaneously quantitated by ribonuclease protection assay and compared with the number of alpha 4 beta 2 receptor subtype, measured by (-)-[3H]nicotine binding in the cerebellum, brain stem, hippocampus, cortex, thalamus and striatum of rat brain. The rank order of abundance of alpha 4 and beta 2 mRNA was different from that of alpha 4 beta 2 receptor subtype levels in the six brain regions studied. The ratio of alpha 4:beta 2 transcripts varied from 2:2.6 to 2:33 in these brain regions. These results reveal a differential co-expression of alpha 4 and beta 2 subunit genes in various regions of rat brain.
ESTHER : Liu_1996_Neuroreport_7_1645
PubMedSearch : Liu_1996_Neuroreport_7_1645
PubMedID: 8904774

Title : Regulation of alpha 4 beta 2 nicotinic acetylcholine receptors in M10 cells following treatment with nicotinic agents - Zhang_1995_Neuroreport_6_313
Author(s) : Zhang X , Gong ZH , Hellstrom-Lindahl E , Nordberg A
Ref : Neuroreport , 6 :313 , 1995
Abstract : The effects of chronic treatment (3 days) with the nicotinic agonists, nicotine and cytisine as well as the antagonists, d-tubocurarine, hexamethonium and dihydro-beta-erythroidine (DH beta E) on alpha 4 beta 2 nicotinic acetylcholine receptors (nAChRs) were investigated in a permanently transfected cell line, M10. The number of alpha 4 beta 2 nAChRs expressed in the cell line was assayed by (-)-[3H]nicotine binding. The two enantiomers of nicotine both significantly increased the number of nAChRs in a concentration dependent manner. No changes in the levels of mRNA for either alpha 4 or beta 2 subunits were found following chronic (-)-nicotine treatment. The effect of (-)-nicotine treatment on the number of nAChRs was partially blocked by the antagonists d-tubocurarine and hexamethonium, but not by dihydro-beta-erythroidine (DH beta E). Chronic exposure of the cells to each of the antagonists did not influence the number of nAChRs. Treatment with the agonist cytisine resulted in a bell-shaped dose-dependent effect on the number of alpha 4 beta 2 nAChRs. In the presence of cytisine (microM) the effect induced by chronic(-)-nicotine treatment on the number of the nAChRs was attenuated. These results indicate that nicotinic agents can induce different regulatory effects in M10 cells due to their individual pharmacological properties as agonist and/or antagonist.
ESTHER : Zhang_1995_Neuroreport_6_313
PubMedSearch : Zhang_1995_Neuroreport_6_313
PubMedID: 7756618

Title : Long-term treatment with tacrine (THA) in Alzheimer's disease--evaluation of neuropsychological data - Amberla_1993_Acta.Neurol.Scand.Suppl_149_55
Author(s) : Amberla K , Nordberg A , Viitanen M , Winblad B
Ref : Acta Neurologica Scandinavica Supplementum , 149 :55 , 1993
Abstract : Long-term effects of tacrine (THA) on cognitive functions of very mild AD patients were studied. The stability of possible positive changes following prolonged treatment and the effect of increased dose was also studied. Three patients were treated with tacrine (80 mg/day) and the effect on cognitive functions was measured with a neuropsychological test battery. Two of the patients (Pats 1 and 4) showed clear positive changes in all parameters measured. The third patient (Pat 5) did not show as clear positive responses. The effect of the initial treatment dose diminished over time. After raising the dose two of the patients showed improvement in cognitive tests reaching their initial level of performance or even better in most of the tests. This positive effect was not as clear in patient 5. After 13 months of tacrine all patients still showed positive changes in some of the tests. Compared to a hypothetical progression curve for untreated AD patients the patients treated with tacrine seemed to have slower progression. In conclusion, it seems that long-term positive effects on cognitive functions of AD patients can be reached with tacrine and it seems to be possible to slow down the progression of the disease. However, to reach long-term positive effects increasing doses seem to be needed. AD patients seem to differ in their response to tacrine.
ESTHER : Amberla_1993_Acta.Neurol.Scand.Suppl_149_55
PubMedSearch : Amberla_1993_Acta.Neurol.Scand.Suppl_149_55
PubMedID: 8128841

Title : Poster: Muscarinic receptor subtypes regulating acetylcholine release in human and rat cortex -
Author(s) : Nilsson-Hakansson L , Svensson A , Alafuzoff I , Nordberg A
Ref : Life Sciences , 52(5-6) :554 , 1993
PubMedID:

Title : Poster: Visualization of muscarinic receptors in Alzheimer brains in vivo by positron emission tomography -
Author(s) : Nordberg A , Hartvig P , Andersson J , Lundqvist H , Vittanen M , Langstrom B , Winblad B
Ref : Life Sciences , 52(5-6) :556 , 1993
PubMedID:

Title : Clinical studies in Alzheimer patients with positron emission tomography - Nordberg_1993_Behav.Brain.Res_57_215
Author(s) : Nordberg A
Ref : Behavioural Brain Research , 57 :215 , 1993
Abstract : Brain imaging techniques will in the future play an important role in the assessment of patients with neurogenerative disorders such as Alzheimer's disease (AD). An early diagnosis of AD is today hampered by lack of reliable diagnostic markers. Positron emission tomography (PET) permits the quantification and three-dimensional imaging of physiological variables. This provides the clinician with a non-invasive imaging technique which allows in vivo quantification of physiological processes in AD underlying dysfunction of cognition. PET studies regarding changes in cerebral blood flow and metabolism are rather consistent at least in moderate/advanced cases of AD. How early in the progress of the disease deficits in these parameters can be observed is still an open question. Longitudinal studies will here be important and especially in individuals with a family history of AD. Since deficits in cholinergic neurotransmission have been measured in autopsy AD brains attempts have also been made to visualized cholinergic activity in vivo. Nicotinic and muscarinic receptors have been visualized in normal and AD brains. A reduced uptake and binding of [11C]nicotine in the temporal and frontal cortices have been measured in AD patients by PET. Few treatment studies in AD have been evaluated by PET. Long-term treatment with the cholinesterase inhibitor tacrine increase the uptake of [11C]nicotine. Significant reduction in uptake between the two enantiomers (S)(-) and (R)(+)-[11C]nicotine has been observed compatible with a restoration of nicotinic receptors. Tacrine also significantly increased the glucose metabolism. PET studies indicate that long-term tacrine treatment in AD patients with mild dementia improves functional activities in brain. When an AD patient with moderate dementia was treated with nerve growth factor (NGF) PET studies revealed increase in cortical blood flow and nicotinic receptors. PET studies will in the future play an important role in the evaluation of new therapeutic drug strategies in AD.
ESTHER : Nordberg_1993_Behav.Brain.Res_57_215
PubMedSearch : Nordberg_1993_Behav.Brain.Res_57_215
PubMedID: 7906947

Title : Poster: Characterization of muscarinic receptor subtypes in normal and Alzheimer brain tissue by using selective muscarinic antagonists -
Author(s) : Svensson A , Alafuzoff I , Nordberg A
Ref : Life Sciences , 52(5-6) :556 , 1993
PubMedID:

Title : Effect of long-term treatment with tacrine (THA) in Alzheimer's disease as visualized by PET - Nordberg_1993_Acta.Neurol.Scand.Suppl_149_62
Author(s) : Nordberg A
Ref : Acta Neurologica Scandinavica Supplementum , 149 :62 , 1993
Abstract : Among various attempts to enhance cholinergic neurotransmission in AD clinical trials with cholinesterase inhibitors have been most promising. In this study positron emission tomography (PET) was used to investigate how long-term treatment with cholinesterase inhibitors like tacrine could induce changes in the functional activity of Alzheimer brains. PET investigations measuring cerebral blood flow, glucose metabolism, nicotinic and muscarinic receptors have repeatedly been performed in patients treated with tacrine up to 2.5 years. Changes in nicotinic receptors and blood flow were observed after 3 weeks of treatment while changes in glucose metabolism were measured after 3 months of treatment. Following longer period of treatments and increase in dose of tacrine improvements were measured by PET. The most significant effects were found in patients with early forms of the dementia. The findings suggest that longer treatment may not only be symptomatic but might slow down the disease process.
ESTHER : Nordberg_1993_Acta.Neurol.Scand.Suppl_149_62
PubMedSearch : Nordberg_1993_Acta.Neurol.Scand.Suppl_149_62
PubMedID: 8128843

Title : In vivo detection of neurotransmitter changes in Alzheimer's disease - Nordberg_1993_Ann.N.Y.Acad.Sci_695_27
Author(s) : Nordberg A
Ref : Annals of the New York Academy of Sciences , 695 :27 , 1993
Abstract : Alzheimer's disease (AD) is characterized by multiple deficits of neurotransmitters in brain. These observations are mainly based upon studies in postmortem brain material where the disease has reached a terminal state. In order to obtain further insight into the early disturbances of the neurotransmitter activities in AD, new imaging techniques such as positron emission tomography (PET) and single positron emission tomography (SPECT) can be applied in vivo for detection of neurotransmitter activity in normal as well as AD brains. Nicotinic receptors have been traced in AD patients by PET and 11C-nicotine at different stages of AD. A lower uptake of (R)(+)- compared to (S)(-)-11C-nicotine was observed in AD patients while the difference in uptake of the two enantiomers was less pronounced in normal individuals. A positive correlation has been observed between cognitive function (Mini-Mental-State-Examination) and uptake of (S)(-)-11C-nicotine in the temporal cortex of AD patients. 11C-benztropine has been used to measure muscarinic receptors in brain by PET. Oral tacrine treatment (80 mg daily) restore nicotinic receptors in AD patients as visualized by PET and 11C-nicotine. Kinetic analysis indicate increased binding of (S)(-)-11C-nicotine after 3 months of treatment with tacrine. The PET data are paralleled by improvement in neuropsychological testings. Intraventricular infusion of nerve growth factor (NGF) to an AD patients for 3 months resulted in an transient increase in uptake and binding of (S)(-)-11C-nicotine in the temporal and frontal cortex and a persistent increase in cortical blood flow.
ESTHER : Nordberg_1993_Ann.N.Y.Acad.Sci_695_27
PubMedSearch : Nordberg_1993_Ann.N.Y.Acad.Sci_695_27
PubMedID: 7902055

Title : [New studies on Alzheimer's disease. Promising therapeutic results with tacrine] -
Author(s) : Nordberg A , Viitanen M , Winblad B
Ref : Lakartidningen , 90 :1561 , 1993
PubMedID: 8483354

Title : Pharmacokinetic studies of cholinesterase inhibitors - Johansson_1993_Acta.Neurol.Scand.Suppl_149_22
Author(s) : Johansson M , Nordberg A
Ref : Acta Neurologica Scandinavica Supplementum , 149 :22 , 1993
Abstract : The pharmacokinetic of some centrally acting cholinesterase inhibitors that have been used to improve memory in patients with dementia of Alzheimer's type, was compared. The original compound in this class, physostigmine has an elimination half-life of 20-30 min. Galanthamine, tacrine and the metabolite 1-hydroxytacrine (velnacrine) have longer elimination half-lives of 1.6-6 hours mainly due to a larger volume of distribution. The concentration of tacrine in the cerebrospinal fluid (CSF) was less than the average plasma concentration in the dosing interval; a ratio of 0.74. The concentration of 1-hydroxytacrine and other metabolites of tacrine in the CSF were higher than the average concentrations of the compounds in plasma.
ESTHER : Johansson_1993_Acta.Neurol.Scand.Suppl_149_22
PubMedSearch : Johansson_1993_Acta.Neurol.Scand.Suppl_149_22
PubMedID: 8128833

Title : EEG regional changes during long-term treatment with tetrahydroaminoacridine (THA) in Alzheimer's disease - Shigeta_1993_Acta.Neurol.Scand.Suppl_149_58
Author(s) : Shigeta M , Persson A , Viitanen M , Winblad B , Nordberg A
Ref : Acta Neurologica Scandinavica Supplementum , 149 :58 , 1993
Abstract : Three patients with Alzheimer's disease of mild type received long-term treatment with THA at doses between 40 mg to 160 mg daily. This study describes the effects of THA on EEG, seen during long-term and high dose treatments. After short-term treatment, the changes of the mean frequency in the temporal and parieto-occipital regions varied between patients, but in the frontal region a significant increase of the mean frequency was seen in all patients. The EEG improvement seen in the frontal region was more significant than that for the other regions at low dose of THA (80 mg). During long-term treatment, we observed different types of EEG changes. The early improvement seen in two patients was temporary and reverted to the pre-treatment value. In a third patient who did not show marked improvement after short-term treatment, an improvement was seen in all regions after longer treatment. Treatment with high doses of THA (120 mg or 160 mg) induced a marked increase in the mean frequency not only in the frontal region but also in the temporal and parieto-occipital regions. Higher doses of THA seem to affect larger areas of the brain than lower doses of THA.
ESTHER : Shigeta_1993_Acta.Neurol.Scand.Suppl_149_58
PubMedSearch : Shigeta_1993_Acta.Neurol.Scand.Suppl_149_58
PubMedID: 8128842

Title : Poster: 1, 2, 3, 4-tetrahydro-9-aminoacridine (THA) may interact with cholinergic presynaptic receptors to regulate in vivo acetylcholine release in the striatum of anesthetized rats -
Author(s) : Zhang X , Xiao WB , Nordberg A
Ref : Life Sciences , 52(5-6) :587 , 1993
PubMedID:

Title : Effect of in vivo microdialysis of 1,2,3,4-tetrahydro-9-aminoacridine (THA) on the extracellular concentration of acetylcholine in the striatum of anesthetized rats - Xiao_1993_J.Pharmacol.Exp.Ther_265_759
Author(s) : Xiao WB , Nordberg A , Zhang X
Ref : Journal of Pharmacology & Experimental Therapeutics , 265 :759 , 1993
Abstract : 1,2,3,4-Tetrahydro-9-aminoacridine (THA, tacrine) is a potent cholinesterase (ChE) inhibitor which is under consideration for the treatment of Alzheimer's disease. This paper examines the effect of in vivo microdialysis of THA, THB-013 (an analog of THA) and physostigmine on the extracellular concentration of acetylcholine (ACh) in the striatum of anesthetized rat, as well as their effects on in vitro striatal ChE activity. In addition, the interaction of THA and physostigmine with cholinergic receptors in rat striatum has been investigated. All three drugs inhibited ChE activity and increased the extracellular concentration of ACh in a concentration-dependent manner. In the presence of THA, atropine induced a smaller increase in extracellular ACh concentrations than it did in the presence of physostigmine, under experimental conditions in which THA (100 microM) and physostigmine (10 microM) produced an equivalent effect on ChE activity. THA bound significantly to both muscarinic and nicotinic receptors in rat striatum, whereas physostigmine did not show significant binding. THA (100 microM) and physostigmine (10 microM) produced an additive effect on the extracellular concentration of ACh, and the addition of THA (10 microM) to physostigmine (1 microM) produced further inhibition of in vitro ChE activity. 4-Aminopyridine (100 microM), a K+ channel blocker, showed no detectable effect by itself on the extracellular concentration of ACh, however, it significantly increased the extracellular concentration of ACh in the presence of physostigmine (10 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
ESTHER : Xiao_1993_J.Pharmacol.Exp.Ther_265_759
PubMedSearch : Xiao_1993_J.Pharmacol.Exp.Ther_265_759
PubMedID: 8496822

Title : Muscarinic and nicotinic receptor changes in the cortex and thalamus of brains of chronic alcoholics - Hellstrom-Lindahl_1993_Brain.Res_620_42
Author(s) : Hellstrom-Lindahl E , Winblad B , Nordberg A
Ref : Brain Research , 620 :42 , 1993
Abstract : The cholinergic system was studied in the cortical and thalamic brain tissues obtained at autopsy from 21 chronic alcoholics and 20 controls. The age related decrease in choline acetyltransferase (ChAT) activity observed in the thalamus of control brains was not found in the corresponding brain areas of chronic alcoholics. A significant decrease in the number of muscarinic receptor binding sites was observed with age in the frontal cortex of both controls and chronic alcoholics when analysed with the nonselective muscarinic antagonist [3H]quinuclidinyl benzilate ([3H]QNB). A significant increase in the number of muscarinic receptor binding sites was observed in the thalamus of controls but not in chronic alcoholics. When the subjects were divided into young (19-57) years, and old (59-84 years) chronic alcoholics marked losses in the total number of muscarinic receptors as well as M1 and M2 receptor subtypes were found in the thalamus of the old group of alcoholics compared to age-matched controls. A coupling of muscarinic receptors to G proteins was observed in thalamic tissues from both controls and chronic alcoholics. Guanylyl-imidodiphosphate (Gpp(NH)p) induced a steepening and rightward shift of the carbachol/[3H]QNB displacement curves performed in membrane preparations of the thalamus from both controls and chronic alcoholics. The number of high affinity nicotinic binding sites in the frontal cortex and thalamus did not differ significantly between controls and chronic alcoholics.
ESTHER : Hellstrom-Lindahl_1993_Brain.Res_620_42
PubMedSearch : Hellstrom-Lindahl_1993_Brain.Res_620_42
PubMedID: 8402197

Title : Poster: Muscarinic and nicotinic receptor changes in the cortex and thalamus of brains of chronic alcoholics -
Author(s) : Hellstrom-Lindahl E , Nordberg A
Ref : Life Sciences , 52(5-6) :555 , 1993
PubMedID:

Title : Tacrine restores cholinergic nicotinic receptors and glucose metabolism in Alzheimer patients as visualized by positron emission tomography - Nordberg_1992_Neurobiol.Aging_13_747
Author(s) : Nordberg A , Lilja A , Lundqvist H , Hartvig P , Amberla K , Viitanen M , Warpman U , Johansson M , Hellstrom-Lindahl E , Bjurling P , et al. , Fasth KJ , Langstrom B , Winblad B
Ref : Neurobiology of Aging , 13 :747 , 1992
Abstract : Three patients with Alzheimer's disease, a 68-year-old woman with mild dementia and 2 men (aged 64 and 72 years) with moderate dementia were treated orally with the cholinesterase inhibitor tacrine (tetrahydroaminoacridine), 80 mg daily, for several months. The patients were investigated using positron emission tomography (PET) prior to, and after 3 weeks and 3 months of treatment. The PET studies involved a multi-tracer system consisting of [18F]-fluoro-deoxy-glucose (18F-FDG) (tracer for glucose metabolism); 11C-butanol (cerebral blood flow) and (S)(-)- and (R)(+)-[N-11C-methyl]-nicotine (nicotinic receptors; cholinergic neural activity). Tacrine treatment increased the uptake of 11C-nicotine to the brain. Significant reduced difference in uptake between the two enantiomers (S)(-)- and (R)(+)11C-nicotine was observed in the frontal and temporal cortices after tacrine treatment in all three patients. The kinetic analysis indicated increased binding of (S)(-)11C-nicotine in brain compatible with a restoration of nicotinic cholinergic receptors. The most pronounced effect was observed after 3 weeks and 3 months treatment in the patient with mild dementia. An increase in cerebral glucose utilization was found in the 68-year-old patient with mild dementia but also slightly in the 64-year-old man with moderate dementia when treated with tacrine for 3 months. Tacrine administration did not affect cerebral blood flow. The PET data obtained after 3 weeks of tacrine treatment was paralleled by improvement in neuropsychological performance. This study shows in vivo by PET neurochemical effects induced in brain by treatment with tacrine to Alzheimer patients. Intervention with tacrine in the early course of the disease might be necessary for clinical improvement.
ESTHER : Nordberg_1992_Neurobiol.Aging_13_747
PubMedSearch : Nordberg_1992_Neurobiol.Aging_13_747
PubMedID: 1491741

Title : THA-A Potential Drug in the Treatment of Alzheimer's Disease -
Author(s) : Nordberg A
Ref : In: Cholinesterases: Structure, Function, Mechanism, Genetics, and Cell Biology , (Massoulie J, Barnard EA, Chatonnet A, Bacou F, Doctor BP, Quinn DM) American Chemical Society, Washington, DC :327 , 1991
PubMedID:

Title : Effect of acute and subchronic nicotine treatment on cortical efflux of [3H]-D-aspartate and endogenous GABA in freely moving guinea-pigs - Beani_1991_Br.J.Pharmacol_104_15
Author(s) : Beani L , Tanganelli S , Antonelli T , Ferraro L , Morari M , Spalluto P , Nordberg A , Bianchi C
Ref : British Journal of Pharmacology , 104 :15 , 1991
Abstract : 1. The [3H]-D-aspartate preloading of the parietal cortex of freely moving guinea-pigs equipped with epidural cups makes it possible to investigate drug effects on the efflux of this radiolabel, assumed as a marker of the glutamatergic structures underlying the cup. In the same model, the efflux of [3H]-gamma-aminobutyric acid ([3H]-GABA) and endogenous GABA can be measured. 2. Nicotine, 0.9-3.6 mg kg-1, s.c., or 3-5 micrograms, i.c.v., increased the efflux of [3H]-D-aspartate but reduced that of GABA. 3. These effects were mediated through mecamylamine-sensitive receptors but the ganglionic blocking agent was devoid of any primary activity. 4. The inhibition of GABA efflux induced by nicotine 3.6 mg kg-1, s.c., was abolished by methysergide 2 mg kg-1, i.p. and was reduced by naloxone 3 mg kg-1, i.p. pretreatment, suggesting the involvement of tryptaminergic and opioid systems. In contrast, muscarinic and catecholamine antagonists were ineffective. 5. Chronic treatment with nicotine (3.6 mg kg-1, twice daily for 16 days) reduced the facilitatory effect of [3H]-D-aspartate and abolished the inhibition of endogenous GABA efflux. 6. A slight increase in the number of nicotinic binding sites (by use of [3H]-nicotine as ligand) was found in the neocortex of chronically treated guinea-pigs. 7. The higher degree of tolerance to chronic nicotine treatment shown by GABA as compared with [3H]-D-aspartate efflux suggests that adaptative changes of the inhibitory neuronal pools prevail. This may contribute to the reinforcing and addictive properties of nicotine.
ESTHER : Beani_1991_Br.J.Pharmacol_104_15
PubMedSearch : Beani_1991_Br.J.Pharmacol_104_15
PubMedID: 1664759

Title : A comparison of the binding of nicotine and nornicotine stereoisomers to nicotinic binding sites in rat brain cortex - Copeland_1991_Naunyn.Schmiedebergs.Arch.Pharmacol_343_123
Author(s) : Copeland JR , Adem A , Jacob P, 3rd , Nordberg A
Ref : Naunyn Schmiedebergs Arch Pharmacol , 343 :123 , 1991
Abstract : Both stereoisomers of nicotine and nornicotine were tested for their ability to competitively displace 3H-(-)-nicotine and 3H-acetylcholine (in the presence of atropine), in rat cortex tissue. 3H-acetylcholine was displaced from two binding sites, super-high and high, by (+)-nicotine, (-)-nornicotine and (+)-nornicotine but from a high affinity site by (-)-nicotine. 3H-nicotine was displaced from two sites, high and low affinity by nicotine and nornicotine stereoisomers. The high-affinity 3H-(-)-nicotine binding site showed similar binding characteristics to one of the sites labelled by 3H-acetylcholine. IC50 values showed (-)-nicotine to be 13 and 25-fold more potent than (+)-nicotine for displacing 3H-(-)-nicotine and 3H-acetylcholine, respectively, but no difference was observed for nornicotine stereoisomers. While (-)-nicotine preferentially bound to the high affinity site of 3H-(-)-nicotine (+)-nicotine preferred the low affinity site. The study provides further evidence for multiple nicotine receptors in brain.
ESTHER : Copeland_1991_Naunyn.Schmiedebergs.Arch.Pharmacol_343_123
PubMedSearch : Copeland_1991_Naunyn.Schmiedebergs.Arch.Pharmacol_343_123
PubMedID: 2067586

Title : Future prospects of research on central cholinergic mechanisms -
Author(s) : Nordberg A , Appel SH , Gottfries CG , Mesulam MM
Ref : Prog Brain Res , 84 :415 , 1990
PubMedID: 2267313

Title : Influence of development and aging on nicotinic receptor subtypes in rodent brain - Zhang_1990_Int.J.Dev.Neurosci_8_715
Author(s) : Zhang X , Wahlstrom G , Nordberg A
Ref : Int J Developmental Neuroscience , 8 :715 , 1990
Abstract : The influence of development and aging on nicotinic receptor subtypes in rodent brain was investigated. 3H-nicotine and 3H-acetylcholine (3H-ACh) were used as receptor ligands. Specific binding sites for 3H-nicotine and 3H-ACh were detected in mouse brain during the late prenatal period. A drop in the number of 3H-nicotine and 3H-ACh binding sites was measured shortly after birth. The 3H-nicotine and 3H-ACh binding sites showed different time courses during prenatal development. Competition experiments using unlabelled (-)nicotine and 3H-nicotine revealed one population of high affinity nicotinic binding sites in the cortex of 1-day and 5-day-old mice whereas both a set of high and low affinity binding sites were found in adult mice. The proportion of cortical high and low affinity nicotinic binding sites did not change with aging although the absolute amount of high affinity nicotinic binding sites decreased. The 3H-nicotine binding showed different temperature dependence in rat brain of different ages. The results illustrate dynamic changes in nicotinic receptor properties during life span of rodents.
ESTHER : Zhang_1990_Int.J.Dev.Neurosci_8_715
PubMedSearch : Zhang_1990_Int.J.Dev.Neurosci_8_715
PubMedID: 2288245

Title : Tetrahydroaminoacridine induces opposite changes in muscarinic and nicotinic receptors in rat brain - Nilsson-Hakansson_1990_Eur.J.Pharmacol_186_301
Author(s) : Nilsson-Hakansson L , Lai Z , Nordberg A
Ref : European Journal of Pharmacology , 186 :301 , 1990
Abstract : Rats were treated with 10 mg/kg tetrahydroaminoacridine (THA) twice daily for 14 days. THA (10 mg/kg) induced a significant decrease in the number of muscarinic receptors (both M1 and M2) in the cortex and striatum, whereas the number of nicotinic receptors in the cortex and hippocampus increased. Rats treated with physostigmine (0.9 mg/kg) showed a reduced number of muscarinic receptors, but no change in nicotinic receptors. The results indicate that treatment with cholinesterase inhibitors can induce opposite changes in brain muscarinic and nicotinic receptors in vivo.
ESTHER : Nilsson-Hakansson_1990_Eur.J.Pharmacol_186_301
PubMedSearch : Nilsson-Hakansson_1990_Eur.J.Pharmacol_186_301
PubMedID: 2289530

Title : Learning deficits in aged rats pretreated chronically with barbital and tested late in abstinence: alleviation by tetrahydroaminoacridine - Mohammed_1990_J.Neural.Transm.Park.Dis.Dement.Sect_2_285
Author(s) : Mohammed AK , Wahlstrom G , Archer T , Nordberg A
Ref : J Neural Transm Park Dis Dement Sect , 2 :285 , 1990
Abstract : Physostigmine and tetrahydroaminoacridine (THA) have been reported to improve cognitive function in patients with Alzheimer's disease. Two experiments were conducted to examine the effects of these anticholinesterase agents on learning in aged rats pretreated chronically with barbital. In the first experiment animals received barbital in their drinking water for 46 weeks. Controls were given only water. On days 100-104 of abstinence, when the animals were 20 months old, acquisition of the Morris maze task was initiated after treatment with physostigmine. It was found that physostigmine improved learning of the maze task in control but not barbital treated rats. In the second experiment animals received barbital solution or water as in experiment one. On days 100-103 of abstinence they were injected with THA before being tested in the Morris water maze. It was found that THA improved learning in both barbital treated and control rats. These results corroborate clinical findings of improved cognitive function following treatment with THA, and suggest that the therapeutic effects of THA may be mediated by mechanisms distinct from cholinesterase inhibition. Furthermore chronic barbital treatment could be used as a model to study cognitive disturbances in experimental animals.
ESTHER : Mohammed_1990_J.Neural.Transm.Park.Dis.Dement.Sect_2_285
PubMedSearch : Mohammed_1990_J.Neural.Transm.Park.Dis.Dement.Sect_2_285
PubMedID: 2078308

Title : New approaches to clinical and postmortem investigations of cholinergic mechanisms -
Author(s) : Nordberg A , Adem A , Nilsson-Hakansson L , Bucht G , Hartvig P , Alafuzoff I , Viitanen M , Langstrom B , Winblad B
Ref : Prog Brain Res , 84 :313 , 1990
PubMedID: 2267305

Title : Effect of acute and subchronic nicotine treatment on cortical acetylcholine release and on nicotinic receptors in rats and guinea-pigs - Nordberg_1989_Br.J.Pharmacol_98_71
Author(s) : Nordberg A , Romanelli L , Sundwall A , Bianchi C , Beani L
Ref : British Journal of Pharmacology , 98 :71 , 1989
Abstract : 1. The effect of acute and chronic (16 days) administration of nicotine on cortical acetylcholine (ACh) release, gross behaviour and brain nicotinic binding sites was investigated in rats and guinea-pigs. 2. The drug, injected either subcutaneously (0.45-0.90 mg kg-1) or intracerebroventricularly (1, 3 and 5 micrograms) increased the cortical ACh release, in a dose-dependent manner, through mecamylamine-sensitive receptors for 1-2 h in both species. 3. Chronic treatment significantly increased basal ACh release in the rat and slightly lowered it in the guinea-pig, but the response to a challenging dose of nicotine was proportionally maintained in both species. 4. The number of nicotinic receptors was four times higher in the rat than in the guinea-pig and was not dependent on the radioligand used ([3H]-nicotine or [3H]-ACh, in the presence of atropine) to determine this. The nicotinic binding sites showed an apparent increase in chronically treated rats but no change in guinea-pigs. 5. Tolerance to the inhibitory effect of the drug, assessed with the T maze test, was found in the rat. No apparent change in gross behaviour was detected in the guinea-pig. 6. It is concluded that chronic nicotine treatment causes evident tolerance to its inhibitory effect on behaviour in the rat, but no adaptation to its excitatory properties on the cholinergic brain structures in rats and guinea-pigs.
ESTHER : Nordberg_1989_Br.J.Pharmacol_98_71
PubMedSearch : Nordberg_1989_Br.J.Pharmacol_98_71
PubMedID: 2804554

Title : Multiple actions of THA on cholinergic neurotransmission in Alzheimer brains - Nordberg_1989_Prog.Clin.Biol.Res_317_1169
Author(s) : Nordberg A , Nilsson-Hakansson L , Adem A , Lai Z , Winblad B
Ref : Prog Clin Biol Res , 317 :1169 , 1989
Abstract : 1,2,3,4-tetrahydro-9-aminoacridine (THA) is a cholinesterase inhibitor presently under investigation in clinical trials for treatment of Alzheimer's disease, senile dementia of Alzheimer type (AD/SDAT). To further analyse the underlying mechanisms for its effect in human brain, an in vitro model which allows measurement of acetylcholine (ACh) release from human postmortem brain slices has been used. In control cortical tissue THA induces a decreased release of ACh probably due to negative feedback mechanisms mediated via presynaptic muscarinic autoreceptors. In AD/SDAT cortex THA enhances the release of ACh to control level. This effect is prevented by nicotinic or muscarinic receptor antagonists, which suggest receptor mechanisms involving both nicotinic and muscarinic receptors. Subchronic treatment of rats with THA (10 mg/kg sc twice daily) or physostigmine (0.9 mg/kg sc five times daily) causes a significant increase in the number of high affinity nicotinic receptors in the cortex of THA treated rats whereas no change is found in the physostigmine treated rats. The number of muscarinic receptors are decreased following both THA and physostigmine treatment.
ESTHER : Nordberg_1989_Prog.Clin.Biol.Res_317_1169
PubMedSearch : Nordberg_1989_Prog.Clin.Biol.Res_317_1169
PubMedID: 2557636

Title : Effect of nicotine on the release of acetylcholine and amino acids in the brain -
Author(s) : Beani L , Bianchi C , Ferraro L , Nilsson L , Nordberg A , Romanelli L , Spalluto P , Sundwall A , Tanganelli S
Ref : Prog Brain Res , 79 :149 , 1989
PubMedID: 2587741

Title : Quantitative autoradiography of nicotinic receptors in large cryosections of human brain hemispheres - Adem_1989_Neurosci.Lett_101_247
Author(s) : Adem A , Nordberg A , Jossan SS , Sara V , Gillberg PG
Ref : Neuroscience Letters , 101 :247 , 1989
Abstract : In vitro quantitative autoradiography was used to visualize nicotinic receptors in large cryosections of human brain hemispheres. Sections 80 microns thick of human brain hemispheres were incubated with (-)-[3H]nicotine and the distribution of nicotinic receptors in human brain was studied. Increasing numbers of nicotinic binding sites were observed in the: hippocampus less than cortex less than cerebellum less than substantia nigra less than putamen less than periaqueductal gray. The cartography of nicotinic receptors in the normal human brain will hopefully be of use in the study of the alteration of these receptors in diseased brain.
ESTHER : Adem_1989_Neurosci.Lett_101_247
PubMedSearch : Adem_1989_Neurosci.Lett_101_247
PubMedID: 2771170

Title : Distribution of nicotinic cholinergic receptors in the rat tel- and diencephalon: a quantitative receptor autoradiographical study using [3H]-acetylcholine, [alpha-125I]bungarotoxin and [3H]nicotine - Harfstrand_1988_Acta.Physiol.Scand_132_1
Author(s) : Harfstrand A , Adem A , Fuxe K , Agnati L , Andersson K , Nordberg A
Ref : Acta Physiologica Scandinavica , 132 :1 , 1988
Abstract : The topographical distribution of [alpha-125I]bungarotoxin [125I]BTX, [3H]nicotine ([3H]Nic), [3H]acetylcholine ([3H]ACh) (in the presence of atropine) binding in rat tel- and diencephalon was investigated using a quantitative receptor autoradiographical technique. With the [3H]ACh and [3H]Nic radioligands, a strong labelling was observed in various thalamic nuclei, including the medial habenula, a moderate labelling in different areas of the cortex cerebri, the nucleus caudatus putamen, the nucleus accumbens and tuberculum olfactorium and a uniform weak labelling in the hypothalamus. When the binding data for [3H]Nic were plotted against binding data for [3H]ACh in various brain nuclei, a significant correlation was obtained. Considering [125I]BTX, the strongest labelling was observed in the lateral mammillary nucleus and the hilus gyrus dentatus of the hippocampal formation. A weak labelling occurred in areas such as the nucleus causatus putamen, the thalamus and the cerebral cortex. No significant correlation was therefore obtained between the degree of [125I]BTX binding in various brain nuclei and the degree of binding observed with [3H]Nic or [3H]ACh. The present results underline the view that the high-affinity [3H]Nic and [3H]ACh binding sites label the same cholinergic nicotinic receptor binding site, while [125I]BTX labels another subpopulation of nicotinic cholinergic receptors, predominantly found in discrete areas of the hypothalamus and the limbic cortex.
ESTHER : Harfstrand_1988_Acta.Physiol.Scand_132_1
PubMedSearch : Harfstrand_1988_Acta.Physiol.Scand_132_1
PubMedID: 3223299

Title : Change in nicotinic receptor subtypes in temporal cortex of Alzheimer brains - Nordberg_1988_Neurosci.Lett_86_317
Author(s) : Nordberg A , Adem A , Hardy J , Winblad B
Ref : Neuroscience Letters , 86 :317 , 1988
Abstract : Competition experiments using (-)-[3H]nicotine and unlabelled nicotine revealed both high and low affinity nicotinic binding sites in temporal cortex of control and Alzheimer (AD/SDAT) brains. A significant reduction in the proportion of high affinity nicotinic binding sites (-20%) and a parallel increase in the proportion of low affinity nicotinic binding sites was obtained in AD/SDAT brain cortex compared to control brain. Moreover, a marked decrease was observed in the affinity of the low affinity nicotinic binding sites in AD/SDAT.
ESTHER : Nordberg_1988_Neurosci.Lett_86_317
PubMedSearch : Nordberg_1988_Neurosci.Lett_86_317
PubMedID: 3380323

Title : Distribution of nicotinic receptors in human thalamus as visualized by 3H-nicotine and 3H-acetylcholine receptor autoradiography - Adem_1988_J.Neural.Transm_73_77
Author(s) : Adem A , Jossan SS , d'Argy R , Brandt I , Winblad B , Nordberg A
Ref : J Neural Transm , 73 :77 , 1988
Abstract : Nicotinic cholinergic receptors in human thalamus were measured using (-)3H-nicotine (20 nM) and 3H-acetylcholine (3H-ACh) (20 nM) as radioligands. The specific binding for 3H-nicotine to homogenates of thalamus was 51.6 +/- 8.3 pmol/g protein and for 3H-ACh 18.6 +/- 1.9 pmol/g protein. Receptor autoradiography indicated a high labelling of both 3H-Nicotine and 3H-ACh in the antero-ventral nucleus of thalamus and dorso-medial nucleus of thalamus, while the labelling was lower in the postero-lateral nucleus of thalamus and in the postero-lateral ventral nucleus of thalamus. Quantitative measurement of the 3H-nicotine autoradiograms showed highest labelling in the anteroventral nucleus of thalamus (17.34 +/- 0.76 pmol/g tissue). This study indicates a heterogeneous distribution of high-affinity nicotinic receptors in the human thalamus.
ESTHER : Adem_1988_J.Neural.Transm_73_77
PubMedSearch : Adem_1988_J.Neural.Transm_73_77
PubMedID: 3404147

Title : Characterization of agonist and antagonist binding to muscarinic cholinergic receptors solubilized from rat cerebral cortex - Adem_1988_J.Neural.Transm_72_11
Author(s) : Adem A , Sabbagh M , Nordberg A
Ref : J Neural Transm , 72 :11 , 1988
Abstract : The muscarinic acetylcholine receptor was solubilized from rat brain cortex by the zwitter-ionic detergent, 3-[3-cholamidopropyl)dimethylamino)-1-propane sulfonate (CHAPS). The supernatant, after centrifugation at 100,000 x g, was shown to contain molecules with binding sites for both 3H-pirenzepine (3H-PZ) and 3H-(-) quinuclidinyl benzilate (3H-QNB). Maximum binding values for 3H-PZ and 3H-QNB binding to solubilized receptors were approximately 176 +/- 24 pmol/g and 370 +/- 53 pmol/g of protein, respectively. The Kd values for 3H-PZ and 3H-QNB binding to solubilized receptors were 27 +/- 6.3 nM and 0.17 +/- 0.03 nM, respectively. The rank order of potencies of muscarinic drugs, in terms of their ability to inhibit binding of either 3H-PZ or 3H-QNB, was atropine greater than pirenzepine greater than oxotremorine greater than carabachol. Pirenzepine inhibited 3H-QNB binding with a Hill coefficient of 0.77, but inhibited 3H-PZ with a Hill coefficient of 0.94. Hill coefficients for agonists were less than 1. These findings indicate that muscarinic receptors solubilized from rat brain cortex retain their abilities to interact selectively with muscarinic receptor agonists and antagonists.
ESTHER : Adem_1988_J.Neural.Transm_72_11
PubMedSearch : Adem_1988_J.Neural.Transm_72_11
PubMedID: 3379385

Title : Subchronic treatment of rats with nicotine: interconversion of nicotinic receptor subtypes in brain - Romanelli_1988_Eur.J.Pharmacol_148_289
Author(s) : Romanelli L , Ohman B , Adem A , Nordberg A
Ref : European Journal of Pharmacology , 148 :289 , 1988
Abstract : A significant increase in the number of cortical high-affinity (-)-[3H]nicotine binding sites was measured in rats treated with nicotine (0.45 mg/kg) twice daily for 18 days. Competition experiments with (-)-[3H]nicotine and various concentrations of unlabelled (-)-nicotine revealed that the proportion of high-affinity nicotine binding sites was significantly increased in the nicotine-treated group while the proportion of low-affinity nicotinic binding sites was similarly significantly reduced compared to the controls. In addition there was a significant decrease in the affinity of both subtypes of nicotinic binding sites.
ESTHER : Romanelli_1988_Eur.J.Pharmacol_148_289
PubMedSearch : Romanelli_1988_Eur.J.Pharmacol_148_289
PubMedID: 3378577

Title : Long-term effects on biotransformation of labelled choline in different parts of the rat brain induced by single choline injections - Nordberg_1988_Pharmacol.Toxicol_62_69
Author(s) : Nordberg A , Wahlstrom G
Ref : Pharmacol Toxicol , 62 :69 , 1988
Abstract : The long-term effects of single choline (Ch) injections on the uptake and metabolism of a tracer dose of 3H-Ch were studied in male rats. Choline was administered as a threshold infusion to obtain convulsions 10 and 4 weeks before sacrifice (group 1). At a single threshold infusion of choline 4 weeks before sacrifice no convulsions were induced in 50% of the animals in a second group (group 2--) whereas convulsions were induced in the remainder of the animals in this group (group 2+). Group 3 contained control animals. One min. after administration of a tracer dose of 3H-Ch the animals were sacrificed and examined for 3H-total activity, 3H-Ch, 3H-acetylcholine (3H-ACh) and 3H-phosphorylcholine (3H-PhCh). These activities were determined in three parts of the brain (cortex, striatum, midbrain + medulla oblongata). In the cortex a significant negative correlation between brain weight and 3H-ACh synthesis was seen in group 1. A comparison between group 2+ and group 2- indicated that induced convulsions were not critical for this effect. In the striatum there was a significant reduction in the total uptake of radioactivity in group 1 and group 2- when values were compared to the control group. Furthermore a significant positive correlation was found between the concentration of radiolabel and 3H-ACh synthesis and a negative relationship with the level of 3H-Ch. In the midbrain preparation the synthesis of 3H-ACh was reduced in group 1 where a significant negative correlation was found between the average threshold dose of choline and both 3H-ACh and 3H-PhCh synthesis.
ESTHER : Nordberg_1988_Pharmacol.Toxicol_62_69
PubMedSearch : Nordberg_1988_Pharmacol.Toxicol_62_69
PubMedID: 3353354

Title : Do tetrahydroaminoacridine (THA) and physostigmine restore acetylcholine release in Alzheimer brains via nicotinic receptors? - Nilsson_1987_J.Neural.Transm_70_357
Author(s) : Nilsson L , Adem A , Hardy J , Winblad B , Nordberg A
Ref : J Neural Transm , 70 :357 , 1987
Abstract : In the presence of 9-amino-1,2,3,4-tetrahydroacridine (THA) 10(-4) M or physostigmine 10(-4) M, the in vitro 3H-Acetylcholine (3H-ACh) release from control cortical slices was significantly reduced. In contrast, THA 10(-4) M and physostigmine 10(-4) M significantly increased the release of 3H-ACh in AD/SDAT brain tissue. This facilitating effect on 3H-ACh release was partially blocked (50%) in the presence of the nicotinic antagonist d-tubocurarine 10(-6) M indicating a possible interaction via nicotinic receptors. The muscarinic antagonist atropine 10(-5) M significantly increased the 3H-ACh release both in control and AD/SDAT brains, thus indicating preservation of muscarinic autoreceptors in the AD/SDAT cortical tissue. In receptor competition studies with 3H-nicotine, 3H-ACh and 3H-quinuclidinyl benzilate (3H-QNB) as receptor ligands, THA interfered with both nicotinic and muscarinic receptor ligand binding, while physostigmine had much less effect.
ESTHER : Nilsson_1987_J.Neural.Transm_70_357
PubMedSearch : Nilsson_1987_J.Neural.Transm_70_357
PubMedID: 3681290

Title : In vitro binding of 3H-acetylcholine to nicotinic receptors in rodent and human brain - Larsson_1987_J.Neural.Transm_69_3
Author(s) : Larsson C , Lundberg PA , Halen A , Adem A , Nordberg A
Ref : J Neural Transm , 69 :3 , 1987
Abstract : The binding of 3H-acetylcholine (3H-ACh) to nicotinic receptors in rodent and human brain was measured in the presence of atropine to prevent binding to muscarinic binding sites. 3H-ACh binds specifically and saturably to rodent brain. From saturation binding Kd was 30 nM in rat cerebral cortex, which is close to that calculated from kinetic experiments. The binding was temperature-dependent, being highest at low temperatures and decreasing at higher temperatures. The regional distribution of binding in mouse brain was not uniform. The binding was highest in the midbrain, intermediate in the cerebral cortex and striatum, and lowest in the cerebellum, hippocampus, hypothalamus and medulla oblongata. No significant correlation was found between the regional 3H-ACh binding and the regional binding of 3H-alpha-bungarotoxin (3H-BTX), 3H-nicotine (3H-NIC), 3H-tubocurarine and the endogenous acetylcholine content, although the correlation value for 3H-ACh/3H-NIC was at the limit for significance. 3H-ACh also bound specifically to human cerebral cortical tissue and this binding was approximately three times lower than in rodent brain, when a low 3H-ACh concentration was used. In contrast to rat brain there appears to exist multiple binding sites for 3H-ACh in human cerebral cortex as suggested by the curvelinear nature of the Scatchard plot. It was calculated that 3H-ACh bound with Kd 4 nM and Bmax 8 pmol/g protein and Kd 112 nM and Bmax 67 pmol/g protein. The Hill number of 1.5 for the binding of low concentration and 2.5 for high concentration of 3H-ACh also suggest that the 3H-ACh-binding sites interaction exhibit positive cooperativity.
ESTHER : Larsson_1987_J.Neural.Transm_69_3
PubMedSearch : Larsson_1987_J.Neural.Transm_69_3
PubMedID: 3585319

Title : Muscarinic receptors in human SH-SY5Y neuroblastoma cell line: regulation by phorbol ester and retinoic acid-induced differentiation - Adem_1987_Brain.Res_430_235
Author(s) : Adem A , Mattsson ME , Nordberg A , Pahlman S
Ref : Brain Research , 430 :235 , 1987
Abstract : The specific binding of the muscarinic ligand [3H](-)quinuclidinyl benzilate [( 3H]QNB) to cell membranes of human SH-SY5Y neuroblastoma cells was studied. Saturation isotherms yielded a Kd = 0.28 +/- 0.06 nM and a Bmax of 337 +/- 47 pmol/g protein. Pirenzepine inhibited [3H]QNB binding; inhibition data showed best fit to a 2-site binding model revealing both a high affinity pirenzepine site (34%, KH = 10 nM) and a low affinity site (66%, KL = 1 microM). These results indicate that muscarinic receptors on SH-SY5Y cells may be subclassified as M1/M2 subtypes. Morphological and biochemical differentiation of these cells after treatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or retinoic acid (RA) resulted in a decrease and an increase in the number of muscarinic binding sites, respectively. Furthermore, TPA- and RA-treated cells showed a significant increase in acetylcholinesterase activity compared with non-treated cells. However, only RA-treated cells showed significant increase in choline acetyltransferase activity compared to non-treated cells. These findings demonstrate that TPA and RA can regulate both the number of muscarinic receptors and the acetylcholinesterase activity in human SH-SY5Y neuroblastoma cells.
ESTHER : Adem_1987_Brain.Res_430_235
PubMedSearch : Adem_1987_Brain.Res_430_235
PubMedID: 3607514

Title : [3H]acetylcholine nicotinic recognition sites in human brain: characterization of agonist binding - Adem_1987_Neurosci.Lett_83_298
Author(s) : Adem A , Synnergren B , Botros M , Ohman B , Winblad B , Nordberg A
Ref : Neuroscience Letters , 83 :298 , 1987
Abstract : In the presence of a cholinesterase inhibitor to prevent hydrolysis and atropine to block muscarinic cholinergic receptors, [3H]acetylcholine ([3H]ACh) binding to human brain membranes showed highest levels of nicotinic binding sites in the thalamus. [3H]ACh, in the presence of atropine, binds to heterogeneous high-affinity binding sites in human thalamus. Scatchard analysis of the binding gave a Kd of 0.58 nM and a Bmax of 3.3 pmol/g protein for the 'super high-affinity' site and a Kd of 27 nM and a Bmax of 70 pmol/g protein for the 'high-affinity' site. Moreover, in competition studies nicotinic agonists such (-)-nicotine and carbachol displaceable [3H]ACh-specific binding sites consist of both a high- and a low-affinity population of sites. These results indicate that highest levels of [3H]ACh binding in human brain were found in the thalamus. Moreover, the human thalamus was found to have multiple high-affinity nicotinic agonist sites.
ESTHER : Adem_1987_Neurosci.Lett_83_298
PubMedSearch : Adem_1987_Neurosci.Lett_83_298
PubMedID: 3441312

Title : Characterization of [3H]-Nicotine Binding in Rodent Brain and Comparison with the Binding of Other Labelled Nicotinic Ligands -
Author(s) : Larsson C , Nordberg A
Ref : Advances in Behavioral Biology , 30 :429 , 1986
PubMedID:

Title : Poster: Changes in muscarinic receptors in normal aging and dementia disorders -
Author(s) : Nordberg A , Adem A , Nilsson L , Winblad B
Ref : Trends in Pharmacological Sciences , Suppl :97 , 1986
PubMedID:

Title : Extraneural cholinergic markers in Alzheimer's and Parkinson's disease - Adem_1986_Prog.Neuropsychopharmacol.Biol.Psychiatry_10_247
Author(s) : Adem A , Nordberg A , Bucht G , Winblad B
Ref : Prog Neuropsychopharmacol Biological Psychiatry , 10 :247 , 1986
Abstract : Muscarinic and nicotinic binding sites were analysed in lymphocytes from patients with Alzheimer's disease, Multi-infarct dementia, Parkinson's disease and age- matched controls. A significant decrease in the number of both muscarinic and nicotinic binding sites was obtained in lymphocytes from Alzheimer patients while in Parkinson patients a significant decrease was found only in the nicotinic binding sites. Using butyrylthiocholine as substrate, no change was observed in cholinesterase activity in plasma from Alzheimer patients, whereas a significant decrease in plasma cholinesterase activity was found in Parkinson patients.
ESTHER : Adem_1986_Prog.Neuropsychopharmacol.Biol.Psychiatry_10_247
PubMedSearch : Adem_1986_Prog.Neuropsychopharmacol.Biol.Psychiatry_10_247
PubMedID: 3797683

Title : A muscarinic receptor type in human lymphocytes: a comparison of 3H-QNB binding to intact lymphocytes and lysed lymphocyte membranes - Adem_1986_Life.Sci_38_1359
Author(s) : Adem A , Nordberg A , Slanina P
Ref : Life Sciences , 38 :1359 , 1986
Abstract : Human blood lymphocytes from normal blood donors exhibited specific binding of the muscarinic antagonist 3H-quinuclidinyl benzilate (3H-QNB). The 3H-QNB binding to intact viable lymphocytes as well as to lysed lymphocyte membranes "P2" was saturable and displaceable by both muscarinic agonists and antagonists. For the lysed lymphocyte membranes "P2" a single binding site with a Bmax of 109 pmol/g protein and a Kd of 15 nM was obtained. Intact viable lymphocytes also showed one binding site with a Kd of 24 nM and a Bmax of 1556 pmol/g protein. The higher Bmax value might be explained in terms of uptake of the ligand when using intact cells or through loss of binding sites when using lysed lymphocyte membranes "P2". IC50 values were lower by a factor of 10(2) for atropine and scopolamine and by 10(4) for pirenzepine when lysed lymphocyte membranes "P2" were used instead of intact viable lymphocytes.
ESTHER : Adem_1986_Life.Sci_38_1359
PubMedSearch : Adem_1986_Life.Sci_38_1359
PubMedID: 3959757

Title : Biochemical and functional basis of putative muscarinic receptor subtypes and its implications. -
Author(s) : Watson M , Roeske WR , Vickroy TW , Smith TL , Akiyama K , Gulya K , Duckles SP , Serra M , Adem A , Nordberg A , Gehlert DR , Wamsley JK , Yamamura HI
Ref : Trends in Pharmacological Sciences , Suppl :46 , 1986
PubMedID:

Title : The Aging of Cholinergic Synapses: Ontogenesis of Cholinergic Receptors -
Author(s) : Nordberg A
Ref : Advances in Behavioral Biology , 30 :165 , 1986
PubMedID:

Title : Modulation of choline transport and acetylcholine synthesis in synaptosomes from different brain regions - Nordberg_1985_Acta.Pharmacol.Toxicol.(Copenh)_56_193
Author(s) : Nordberg A , Sundwall A
Ref : Acta Pharmacologica et Toxicologica (Copenh) , 56 :193 , 1985
Abstract : Uptake and biotransformation of radioactive choline (3H-Ch) have been studied in P2 fractions from different brain regions of mice treated with different doses of sodium pentobarbital (45-120 mg/kg intraperitoneally) or saline. Sodium dependent uptake (SDU) has been measured as the difference between results of incubations with Na+ in the incubation medium and when the sodium salts were replaced by Trisphosphate and sucrose. The uptake of radioactivity increased during the incubation with 3H-Ch but the proportion of 3H-ACh was the same at all time points. The proportion of 3H-ACh to 3H-Ch in the P2 pellet was 86, 81 and 69 per cent in hippocampus, striatum and cortex, respectively. Omission of sodium ions in the incubation medium reduced uptake of 3H-Ch by about 90 per cent at 1 microM Ch in the incubation medium and the proportion of 3H-ACh to 3H-Ch was only 10 to 20 per cent while the proportion of 3H-PhCh increased from insignificant amounts to between 20 to 30 per cent. There were quantitative regional differences in SDU, a two times greater uptake was obtained in the striatum compared with cortex and hippocampus. Apparent Km and Vmax were 0.9 X 10(-6)M and 71 pmol/mg, respectively, for the cortex of untreated animals. The contribution of endogenous Ch from the P2 fraction to the incubation medium gave a final concentration of 0.5 microM Ch in the standard uptake experiments. The 3H-Ch uptake was significantly reduced in P2 fraction from cortex and hippocampus prepared from mice anaesthetized with sodium pentobarbital while the uptake in P2 fractions from the striatum was unaffected. Sodium pentobarbital treatment did not affect the proportion of 3H-ACh in the pellets.
ESTHER : Nordberg_1985_Acta.Pharmacol.Toxicol.(Copenh)_56_193
PubMedSearch : Nordberg_1985_Acta.Pharmacol.Toxicol.(Copenh)_56_193
PubMedID: 4013759

Title : Muscarinic binding sites in small homogenates and in autoradiographic sections from rat and human spinal cord - Gillberg_1984_Brain.Res_300_327
Author(s) : Gillberg PG , Nordberg A , Aquilonius SM
Ref : Brain Research , 300 :327 , 1984
Abstract : Binding of labelled L- quinuclidinylbenzylate was studied in cryosections and homogenates of human and rat spinal cord. For the cryosections an autoradiographic method was used. With both techniques a higher density of muscarinic binding sites was found in rat than in human spinal cord. In the autoradiographs very high densities of muscarinic binding sites were observed in the motor neurone area and in the apical part of the dorsal horn. The latter high density region was not always found in homogenates from dissected tissue samples. The autoradiographic technique has a better resolution for detecting discrete regional variations in the receptor content of the spinal cord.
ESTHER : Gillberg_1984_Brain.Res_300_327
PubMedSearch : Gillberg_1984_Brain.Res_300_327
PubMedID: 6733476

Title : Biochemical changes in dementia disorders of Alzheimer type (AD\/SDAT) - Gottfries_1983_Neurobiol.Aging_4_261
Author(s) : Gottfries CG , Adolfsson R , Aquilonius SM , Carlsson A , Eckernas SA , Nordberg A , Oreland L , Svennerholm L , Wiberg A , Winblad B
Ref : Neurobiology of Aging , 4 :261 , 1983
Abstract : In postmortem investigations of patients with dementia of Alzheimer type (AD/SDAT) (n = 14) the brain weight was significantly reduced when compared to controls (n = 16). In four AD/SDAT-brain parts investigated the concentrations of 5-hydroxy-tryptamine and noradrenaline were significantly reduced while 3-methoxy-4-hydroxyphenylglycol was significantly increased. In the caudate nucleus of the AD/SDAT-brains the concentrations of dopamine and homovanillic acid were significantly reduced. The activity of monoamine oxidase B was increased suggesting a proliferation of extra neuronal tissue in the AD/SDAT-brains. The activity of choline acetyl transferase was reduced in the four brain parts investigated, showing a general reduction in the acetylcholine system in the AD/SDAT-brains. The ganglioside concentration was significantly reduced suggesting a reduced density of nerve endings in the demented brains. The AD/SDAT-group was according to rating scales severely demented. Patients with an early onset of the dementia disease were more severely intellectually reduced and had more pronounced biochemical disturbances than those with a late onset of the dementia.
ESTHER : Gottfries_1983_Neurobiol.Aging_4_261
PubMedSearch : Gottfries_1983_Neurobiol.Aging_4_261
PubMedID: 6200784

Title : Pharmacodynamic effects of nicotine and acetylcholine biosynthesis in mouse brain - Nordberg_1983_Acta.Pharmacol.Toxicol.(Copenh)_52_341
Author(s) : Nordberg A , Sundwall A
Ref : Acta Pharmacologica et Toxicologica (Copenh) , 52 :341 , 1983
Abstract : Nicotine (4; 8 mg/kg) given intraperitoneally to mice had a marked hypothermic effect with a duration of more than 2 hours. Mecamylamine (0.5; 2.5 mg/kg) prevented the hypothermic effect of 2 mg/kg nicotine but had no effect on 4 mg/kg nicotine. Atropine (5 mg/kg) did not affect the hypothermia produced by nicotine. Other symptoms induced by nicotine (0.5-4 mg/kg) were convulsions, rigidity, tremor and decrease in motor activity. Pretreatment with mecamylamine (0.5 mg/kg) prevented convulsions but had only a slight effect on the decreased motor activity. Atropine pretreatment was ineffective. It thus seems as if the effects of nicotine at least to some part are mediated by nicotine-like receptors. When a tracer dose of labelled choline (3H-Ch) was given to mice treated with nicotine (4 mg/kg) a marked increase (+100%) in the biosynthesis of labelled acetylcholine (ACh) in the striatum was found when the animals were killed by decapitation. If the mice were killed by a more rapid technique, microwave irradiation of the head, no change in 3H-ACh formation was observed in comparison to controls. The findings indicate that nicotine can preserve a very labile pool of newly synthesized ACh in the striatum.
ESTHER : Nordberg_1983_Acta.Pharmacol.Toxicol.(Copenh)_52_341
PubMedSearch : Nordberg_1983_Acta.Pharmacol.Toxicol.(Copenh)_52_341
PubMedID: 6880769

Title : Effect of denervation on acetylcholine synthesizing activity and nicotine-like binding sites in rat hind limb muscles - Aquilonius_1982_Acta.Physiol.Scand_114_345
Author(s) : Aquilonius SM , Askmark H , Eckernas SA , Nordberg A
Ref : Acta Physiologica Scandinavica , 114 :345 , 1982
Abstract : The acetylcholine synthesizing (ACh-s) activity and the binding of the nicotine ligands 3H-alpha-bungarotoxin (alpha Btx) and 3H-d-tubocurarine (d-TC) were analysed in rat hind limb muscles 1-32 days after denervation. Muscles of the contralateral leg served as controls. ACh-s activity was considerably lower in tibialis anterior as compared to the extensor digitorum longus and the peroneus longus muscles. After denervation there was a rapid decrease in ACh-s activity in parallel to a considerable increase in alpha-Btx binding. The binding of d-TC was essentially unchanged following denervation indicating the special characteristics of the newly formed receptors. ACh-s activity can be differentiated into one specific (choline acetyltransferase) and one unspecific component.
ESTHER : Aquilonius_1982_Acta.Physiol.Scand_114_345
PubMedSearch : Aquilonius_1982_Acta.Physiol.Scand_114_345
PubMedID: 7136765

Title : Chronic Barbital Treatment and Cholinergic Mechanisms in Brain -
Author(s) : Nordberg A , Wahlstrom G
Ref : Advances in Behavioral Biology , 25 :809 , 1981
PubMedID:

Title : Interaction between Atropine and Hexobarbital in the Abstinence after Chronic Barbital Treatments in the Rat -
Author(s) : Wahlstrom G , Nordberg A
Ref : Advances in Behavioral Biology , 25 :819 , 1981
PubMedID:

Title : Search for Nicotine-Like Receptor Binding Sites in Brain -
Author(s) : Nordberg A , Larsson C
Ref : Advances in Behavioral Biology , 25 :639 , 1981
PubMedID:

Title : Changes in cholinergic function in rat brain late in abstinence after chronic barbital treatment - Nordberg_1981_Drug.Alcohol.Depend_7_51
Author(s) : Nordberg A , Wahlstrom G
Ref : Drug Alcohol Depend , 7 :51 , 1981
Abstract : The effect of a forced long-term barbital treatment (daily dosage about 200 mg/kg for 32 weeks) on cholinergic brain mechanisms was studied on days 53 and 81 - 83 after withdrawal. Some of the barbital-treated rats were given a single injection of atropine (8 mg/kg intraperitoneally) on the third day of abstinence (group BA), while the other barbital-treated rats received saline (group BS). The sensitivity to a threshold dose of choline was tested on day 53. The rats in the BS group were more sensitive to choline than those in the control groups. When the rats were sacrificed on day 81 - 83 after withdrawal, a significant reduction in brain weight was found in group BS but not in group BA when compared with the controls. At the same time the content of endogenous acetylcholine was reduced in the barbital-treated animals and this reduction seemed to be positively related to the reduction of brain weight. After sacrifice the uptake and biotransformation of a tracer dose of radioactive choline were also studied. A marked difference was seen between the brain regions. In the cortex the biosynthesis of radioactive acetylcholine was significantly lower in the BS group than in the control group; the BA group was in between. In the midbrain no significant changes in radioactive acetylcholine synthesis were seen. In the striatum a significantly lower formation of radioactive acetylcholine was found in the BA group and a lower radioactive phosphorylcholine formation in he BS group. The studied variables indicate that prolonged barbital treatment induces changes in cholinergic function in rat brain extending considerably beyond withdrawal. Treatment with atropine early in the abstinence seemed to reduce these changes.
ESTHER : Nordberg_1981_Drug.Alcohol.Depend_7_51
PubMedSearch : Nordberg_1981_Drug.Alcohol.Depend_7_51
PubMedID: 7215155

Title : Assessment of cholinergic neuronal activity in the brain - Nordberg_1980_Acta.Physiol.Scand.Suppl_479_7
Author(s) : Nordberg A , Sundwall A
Ref : Acta Physiologica Scandinavica Suppl , 479 :7 , 1980
Abstract : Endogenous acetylcholine (ACh), ACh turnover and high affinity choline uptake (H.A. Ch uptake) have all been considered valuable markers for cholinergic neural activity. The present communication compare the markers regarding regional differences in the brain of normal mice as well as in mice treated with oxotremorine (OT), nicotine and sodium pentabarbital. A relationship is obtained between in vivo turnover values for 5 different brain regions and in vitro H.A. Ch uptake. Pretreatment with OT and sodium pentobarbital produces specific regional changes in both turnover and H.A. Ch uptake. However, both drugs produce shifts of the correlation lines due to uptake being less affected than turnover. Atropine completely prevented the effects of OT regarding turnover and H.A. Ch uptake. A convulsant dose of nicotine did not produce significant changes in any of the brain regions studied neither on turnover nor on H.A. Ch uptake.
ESTHER : Nordberg_1980_Acta.Physiol.Scand.Suppl_479_7
PubMedSearch : Nordberg_1980_Acta.Physiol.Scand.Suppl_479_7
PubMedID: 6932808

Title : Acute and chronic effects of barbiturates on regional turnover of acetylcholine in brain - Nordberg_1980_Adv.Exp.Med.Biol_126_165
Author(s) : Nordberg A , Wahlstrom G
Ref : Advances in Experimental Medicine & Biology , 126 :165 , 1980
Abstract : Data concerning both the acute and chronic effects of barbiturates on acetylcholine [ACh] turnover in mouse and rat brain are presented. A single anaesthetic dose of pentobarbital [60 mg/kg, i.p.] to mice increased the endogenous content of ACh and decreased the turnover of ACh in the hippo-campus and cortex. No effect was found in the striatum. At sacrifice after chronic treatment with barbital to rats for about 30 weeks no effect was found on the endogenous ACh content. 3 days after the barbital solution was replaced by water [at the day with maximal number of abstinence convulsions] the amount of endogenous ACh was decreased by 35% in the striatum in comparison with control and the decrease was still significant after 30 days of abstinence. The biosynthesis of radioactive ACh from a tracer dose of radioactive choline [Ch] was increased in the cerebellum+midbrain+medulla oblongata of rats receiving barbital until sacrifice and rats abstinent for 3 days. It was also increased in the hippocampus+cortex on the 3rd abstinent day. No significant effect on the ACh formation was found in the striatum. Calculation of the specific radioactivity [SA] of ACh showed an increased SA in all brain regions in the abstinence indicating that the turnover of ACh might be increased during the abstinence after long-term barbital treatment. An increased number of muscarinic binding sites [measured by quinuclidinyl benzilate, QNB, as ligand] was also found in synapotosomes from the striatum of rats abstinent for 3 days.
ESTHER : Nordberg_1980_Adv.Exp.Med.Biol_126_165
PubMedSearch : Nordberg_1980_Adv.Exp.Med.Biol_126_165
PubMedID: 7405683

Title : Regional biosynthesis of acetylcholine in brain following forced oral chronic barbitone treatment to rat -
Author(s) : Nordberg A , Wahlstrom G
Ref : Journal of Neurochemistry , 32 :371 , 1979
PubMedID: 762554

Title : Modulation of Acetylcholine Turnover in Brain Regions -
Author(s) : Nordberg A , Sundwall A
Ref : Advances in Behavioral Biology , 24 :629 , 1978
PubMedID:

Title : Effect of sodium pentobarbital on the apparent turnover of acetylcholine in different brain regions - Nordberg_1977_Acta.Physiol.Scand_99_336
Author(s) : Nordberg A , Sundwall A
Ref : Acta Physiologica Scandinavica , 99 :336 , 1977
Abstract : The turnover rate of acetylcholine(ACh)was measured in six different brain regions in the mouse following pulse injection of radioactive choline (Ch) and killing of the animals by microwave irradiation of the head (0.25 s, 5 kW). The time course of the change in 3H-ACh/3H-Ch ratio was linear 0-06 s in all brain regions after administration of 3H-Ch. Plots of the specific radioactivities (SA) of ACh and Ch versus time indicate a precursor-product relationship in all brain regions except the cerebellum both in control and sodium pentobarbital anesthesized animals. The turnover was highest in the striatum (55 nmol-g-1-min-1), while in the cortex and hippocampus this value was approximately half (27 and 21 nmol-g-1-min-1). In the midbrain and medulla oblongata the turnover rates were only 11 and 10 nmol-g-1-min-1. Sodium pentobarbital anesthesia reduced specifically the turnover in the cortex and hippocampus to about 60 to 70 percent.
ESTHER : Nordberg_1977_Acta.Physiol.Scand_99_336
PubMedSearch : Nordberg_1977_Acta.Physiol.Scand_99_336
PubMedID: 848306

Title : Effect of long-term forced oral barbital administration on endogenous acetylcholine in different regions of rat brain - Nordberg_1977_Eur.J.Pharmacol_43_237
Author(s) : Nordberg A , Wahlstrom G
Ref : European Journal of Pharmacology , 43 :237 , 1977
Abstract : Rats received a solution of sodium barbital as their only drinking fluid for 25 and 30 weeks. Four groups were studied: (1) control; (2) barbital until sacrifice; (3) barbital withheld (abstinent) for 3 days; (4) abstinent for 12 days. Abstinence convulsions in groups 3 and 4 were recorded with jiggle cages. The rats were killed by decapitation and the concentration of acetylcholine (ACh) was measured in 3 parts of the brain: striatum, hippocampus + cerebral cortex, cerebellum + medulla oblongata + midbrain. In animals receiving barbital until sacrifice, no significant change in ACh content was found in any of the brain regions compared with controls. In animals abstinent for 3 days and with a maximal frequency of spontaneous convulsions a decreased content of ACh (--35%) was found in the striatum. On the 12th day of abstinence, when the convulsive activity clearly had decreased, the ACh content was still decreased (--30%) in the striatum and a significant decrease compared with controls was also found in the cerebellum + medulla oblongata + midbrain.
ESTHER : Nordberg_1977_Eur.J.Pharmacol_43_237
PubMedSearch : Nordberg_1977_Eur.J.Pharmacol_43_237
PubMedID: 559577

Title : Biosynthesis of acetylcholine in different brain regions in vivo following alternative methods of sacrifice by microwave irradiation - Nordberg_1976_Acta.Physiol.Scand_98_307
Author(s) : Nordberg A , Sundwall A
Ref : Acta Physiologica Scandinavica , 98 :307 , 1976
Abstract : Endogenous acetylcholine and biotransformation of tritium-labelled choline (3H-CH) were studied in mouse brain regions following different methods of sacrifice, viz. dislocation of the spine (7 min until enzymes inactivated), whole body microwave irradiation (7 s) and irradiation of the head (0.25 s). The brain temperature was measured in different locations 10 to 60 s after irradiation. The slope of the temperature time curves indicated a brain temperature of about 85-90 degrees C at the termination of exposure to both types of irradiation. Acetylcholinesterase (AChE) and choline acetyltransferase (CAT) were practically completely inactivated when measured one to two min after sacrifice. For turnover studies, mice were killed 1, 5, 10 or 20 min after i.v. injection of 15 nmol of 3H-Ch. The brains were dissected into 6 regions, extracted and analysed. No significant difference (except in cortex) in the amount of endogenous ACh was found when whole body irradiation was used in comparison to dislocation of the spine. However, the amount of 3H-acetylcholine (3H-ACh) was much higher in the striatum, hippocampus and cortex, in particular. With the shorter inactivation time (head irradiation) endogenous ACh was markedly increased in the striatum, cortex, medulla, oblongata and midbrain. However, there was no further increase in the radioactive ACh. The difference regarding the post-mortem sensitivity of endogenous and radioactive ACh does not seem to have been due to methodological artifacts but rather suggests that they are handled differently by the brain tissue. Plots of the specific radioactivity (SA) of Ch and ACh vs. time indicated fairly distinct precursor-product relationship in the different regions, when the animals were sacrificed by irradiation of the head.
ESTHER : Nordberg_1976_Acta.Physiol.Scand_98_307
PubMedSearch : Nordberg_1976_Acta.Physiol.Scand_98_307
PubMedID: 998280

Title : Effect of oxotremorine on endogenous acetylcholine and on uptake and biotransformation of radioactive choline in discrete regions of mouse brain in vivo -
Author(s) : Nordberg A , Sundwall A
Ref : Biochemical Pharmacology , 25 :135 , 1976
PubMedID: 1259775

Title : Effect of pentobarbital on endogenous acetylcholine and biotransformation of radioactive choline in different brain regions -
Author(s) : Nordberg A , Sundwall A
Ref : Cholinergic.Mechanisms, Raven Press :229 , 1975
PubMedID: